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Zhang L, Yuan J, Yao S, Wen G, An J, Jin H, Tuo B. Role of m5C methylation in digestive system tumors (Review). Mol Med Rep 2025; 31:142. [PMID: 40183387 PMCID: PMC11979572 DOI: 10.3892/mmr.2025.13507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Abstract
Currently, the incidence of digestive system tumors has been increasing annually, thus becoming a prevalent cause of cancer‑related mortalities. Although significant strides have been made in targeting the molecular mechanisms that underpin the development of these tumors, their treatment and prognosis still pose substantial challenges. This is primarily due to the ambiguity of early diagnostic indicators and the fact that most digestive system tumors are detected at an advanced stage. However, epigenetic modifications are capable of altering the expression of oncogenes and regulating biological processes in cancer. In recent years, the study of methylation in relation to tumor pathogenesis has become a focus of prominent research. Among the various types of methylation, 5‑methylcytosine (m5C) methylation plays a crucial role in the development of digestive system tumors and is anticipated to serve as a novel therapeutic target. However, to date, a comprehensive and systematic review concerning the role of m5C methylation in digestive system tumors is lacking. Consequently, the present study reviewed the role of m5C methylation in digestive system tumors such as esophageal cancer, gastric cancer and hepatocellular carcinoma, with the aim of providing a valuable reference for future research endeavors.
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Affiliation(s)
- Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jianbo Yuan
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P.R. China
| | - Shun Yao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jiaxing An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Jiang J, Liu F, Cui D, Xu C, Chi J, Yan T, Guo F. Novel molecular mechanisms of immune evasion in hepatocellular carcinoma: NSUN2-mediated increase of SOAT2 RNA methylation. Cancer Commun (Lond) 2025. [PMID: 40227950 DOI: 10.1002/cac2.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/13/2025] [Accepted: 03/17/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a deadly malignancy known for its ability to evade immune surveillance. NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase involved in carcinogenesis, has been associated with immune evasion and energy metabolism reprogramming. This study aimed to examine the molecular mechanisms underlying the involvement of NSUN2 in immune evasion and metabolic reprogramming of HCC. METHODS Single-cell transcriptomic sequencing was applied to examine cellular composition changes, particularly immune cell dynamics, in HCC and adjacent normal tissues. Bulk RNA-seq and proteomics identified key genes and proteins. Methylation sequencing and methylated RNA immunoprecipitation (MeRIP) were carried out to characterize the role of NSUN2 in 5-methylcytosine (m5C) modification of sterol O-acyltransferase 2 (SOAT2). Clinical samples from 30 HCC patients were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blotting. Gene expression was manipulated using CRISPR/Cas9 and lentiviral vectors. In vitro co-culture models and metabolomics were used to study HCC cell-T cell interactions, energy metabolism, and immune evasion. Tumor growth in an orthotopic mouse model was monitored by bioluminescence imaging, with subsequent measurements of tumor weight, volume, and immunohistochemical staining. RESULTS Single-cell transcriptomic analysis identified a marked increase in malignant cells in HCC tissues. Cell communication analysis indicated that tumor cells might promote cancer progression by evading immune clearance. Multi-omics analyses identified NSUN2 as a key regulator in HCC development. MeRIP confirmed that NSUN2 facilitated the m5C modification of SOAT2. Analysis of human HCC tissue samples demonstrated pronounced upregulation of NSUN2 and SOAT2, along with elevated m5C levels in HCC tissues. In vitro experiments uncovered that NSUN2 augmented the reprogramming of energy metabolism and repressed the activity and cytotoxicity of CD8+ T cells, contributing to immune evasion. In vivo studies further substantiated the role of NSUN2 in fostering immune evasion and tumor formation of HCC by modulating the m5C modification of SOAT2. CONCLUSIONS The findings highlight the critical role of NSUN2 in driving HCC progression through the regulation of m5C modification on SOAT2. These findings present potential molecular markers for HCC diagnosis and therapeutic targets for its treatment.
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Affiliation(s)
- Jinhua Jiang
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
- Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Feng Liu
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Dan Cui
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Caixia Xu
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Jiachang Chi
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Tinghua Yan
- The First Clinical Medical College of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Fang Guo
- Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, P. R. China
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Zhou X, Liu W, Liang Z, Liang J, Zhang T, Gao W, Yang Z. Key epigenetic enzymes modulated by natural compounds contributes to tumorigenicity. Int J Biol Macromol 2025; 301:140391. [PMID: 39880237 DOI: 10.1016/j.ijbiomac.2025.140391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/21/2025] [Accepted: 01/26/2025] [Indexed: 01/31/2025]
Abstract
Dysregulation of epigenetic regulation is observed in numerous tumor cells. The therapeutic effects of natural products on tumors were investigated through a comprehensive analysis of active ingredients derived from various structured natural products. The analysis focuses on regulating key enzymes involved in epigenetic control. To study the modulation of these enzymes for tumor treatment, the structural characteristics of natural products that impact tumorigenesis were identified. The presence of specific patterns suggests that compounds sharing structural similarities can potentially induce therapeutic effects on identical tumors through modulation of distinct modifying enzymes. Structurally analogous natural products can likewise achieve therapeutic effects across diverse tumor types via their interaction with a common epigenetic enzyme. There exist numerous flavonoids with the capability to modulate METTL3, thereby influencing the development of various tumors. The normalization process was implemented to account for a common phenomenon, wherein structurally distinct compounds effectively target the same tumor by modulating a shared key enzyme. By summarizing, valuable insights into the role of compound-epigenetic enzymes in tumor development have been obtained. This discovery establishes a crucial scientific foundation for the prevention and treatment of tumor development through the utilization of structurally similar natural active ingredients.
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Affiliation(s)
- Xiaoyue Zhou
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wanqing Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ziqi Liang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiali Liang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenyi Gao
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Zizhao Yang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of General Surgery, Shanghai Seventh People's Hospital, Shanghai 200137, China.
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Yang Y, Cao L, Xu X, Li D, Deng Y, Li L, Zeng B, Jiang H, Shan L, Huang Y, Xu Y, Ma L. NSUN2/ALYREF axis-driven m 5C methylation enhances PD-L1 expression and facilitates immune evasion in non-small-cell lung cancer. Cancer Immunol Immunother 2025; 74:132. [PMID: 40029463 PMCID: PMC11876480 DOI: 10.1007/s00262-025-03986-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/17/2025] [Indexed: 03/05/2025]
Abstract
Non-small-cell lung cancer (NSCLC) represents a highly prevalent form of malignancy. 5-methylcytosine (m5C) methylation functions as a key post-transcriptional regulatory mechanism linked to cancer progression. The persistent expression of PD-L1 in tumor cells plays a pivotal role in facilitating immune evasion and promoting T-cell exhaustion. However, the involvement of m5C in NSCLC immune evasion remains inadequately understood. This study seeks to explore the function of the m5C methyltransferase NSUN2 in modulating PD-L1 expression and facilitating immune evasion in NSCLC. Our findings indicate elevated levels of NSUN2 and ALYREF in NSCLC, and both promote the growth of NSCLC cells and the progression of lung cancer. Moreover, the expression of PD-L1 in NSCLC tissues positively correlates with NSUN2 and ALYREF expression. We then discovered that PD-L1 acts as a downstream target of NSUN2-mediated m5C modification in NSCLC cells. Knocking down NSUN2 significantly reduces m5C modification of PD-L1 mRNA, thereby decreasing its stability via the m5C reader ALYREF-dependent manner. Furthermore, inhibiting NSUN2 enhanced CD8+ T-cell activation and infiltration mediated by PD-L1, thereby boosting antitumor immunity, as confirmed in both in vitro and in vivo experiments. Collectively, these results suggested that NSUN2/ALYREF/PD-L1 axis plays a critical role in promoting NSCLC progression and tumor cell immune suppression, highlighting its potential as a novel therapeutic strategy for NSCLC immunotherapy.
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Affiliation(s)
- Yiran Yang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Leiqun Cao
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Xin Xu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Dan Li
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Yiran Deng
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Lan Li
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Bingjie Zeng
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Haixia Jiang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Liang Shan
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Yiwen Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China
| | - Yunhua Xu
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China.
| | - Lifang Ma
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241 West Huaihai Road, Shanghai, 200030, China.
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Tong R, Li Y, Wang J, Liu C, Liu Y, Li R, Wang X. NSUN2 Knockdown Promotes the Ferroptosis of Colorectal Cancer Cells Via m5C Modification of SLC7A11 mRNA. Biochem Genet 2025:10.1007/s10528-025-11035-0. [PMID: 39920526 DOI: 10.1007/s10528-025-11035-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/12/2025] [Indexed: 02/09/2025]
Abstract
The high occurrence and death rates of colorectal cancer (CRC) make it a major health concern. Recent studies have identified NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase, as a key regulator in various tumor types. However, how exactly NSUN2-mediated m5C alteration affects CRC is still a mystery. This study seeks to understand how NSUN2 contributes to the growth and death of colorectal cancer cells. New tissue samples were taken in order to investigate NSUN2 expression in CRC. In vitro tests were performed to evaluate NSUN2's function. We used m5C-methylated-RNA immunoprecipitation and RNA stability experiments to find out how NSUN2 works on Solute carrier family 7 member 11 (SLC7A11, also called xCT). Downregulation of NSUN2 limits CRC cell growth and induces ferroptosis, as we show that NSUN2 was substantially expressed in CRC. In terms of the molecular mechanism, NSUN2 controls the translation and stability of SLC7A11 mRNA by regulating its m5C methylation. Functional tests show that SLC7A11 compensates for the NSUN2 knockdown-induced decrease in cell proliferation. Additionally, SLC7A11 overexpression restores ferroptosis to CRC cells after NSUN2 knockdown. These findings emphasize NSUN2's crucial role in modulating colorectal cancer cell growth and survival via SLC7A11, pointing to promising new therapeutic targets.
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Affiliation(s)
- Ruibing Tong
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China.
| | - Yuefeng Li
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China
| | - Junli Wang
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China
| | - Chengyu Liu
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China
| | - Yan Liu
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China
| | - Rongshuang Li
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China
| | - Xinghong Wang
- Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China
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Lou N, Gu X, Fu L, Li J, Xue C. Significant roles of RNA 5-methylcytosine methylation in cancer. Cell Signal 2025; 126:111529. [PMID: 39615772 DOI: 10.1016/j.cellsig.2024.111529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/19/2024] [Accepted: 11/24/2024] [Indexed: 12/06/2024]
Abstract
Cancer stands as a leading cause of mortality and poses an escalating threat to global health. Epigenetic dysregulation is pivotal in the onset and advancement of cancer. Recent research on RNA 5-methylcytosine (m5C) methylation has underscored its significant role in cancer. RNA m5C methylation is a key component in gene expression regulation and is intricately linked to cancer development, offering valuable insights for cancer diagnosis, treatment, and prognosis. This review provides an in-depth examination of the three types of regulators associated with RNA m5C methylation and their biological functions. It further investigates the expression and impact of RNA m5C methylation and its regulators in cancer, focusing on their mechanisms in cancer progression and clinical relevance. The current research on inhibitors targeting RNA m5C methylation-related regulators remains underdeveloped, necessitating further exploration and discovery.
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Affiliation(s)
- Na Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471000, Henan, China
| | - Leiya Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
| | - Chen Xue
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
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7
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Wang Z, Li J, Wang F, Cheng C, Wu X, Guo W, Li C, Luo Y, Zhang G, Zhang S, Hou J, Wang W, Wang S. m 5C related-regulator-mediated methylation modification patterns and prognostic significance in breast cancer. Sci Rep 2024; 14:27477. [PMID: 39523404 PMCID: PMC11551150 DOI: 10.1038/s41598-024-77389-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
5-Methylcytosine (m5C) is closely associated with cancer. However, the role of m5C in breast cancer(BC)remains unclear. This study combined single-cell RNA sequencing (scRNA-Seq) and transcriptomics datasets to screen m5C regulators associated with BC progression and analyze their clinical values. Firstly, This study elucidates the mechanisms of the m5C landscape and the specific roles of m5C regulators in BC patients. we found that the dysregulation of m5C regulators with m5Cscore play the essential role of the carcinogenesis and progression in epithelial cells and myeloid cells of BC at single cell level. External validation was conducted using an independent scRNA-Seq datasets. Then, three distinct m5C modification patterns were identified by transcriptomics datasets. Based on the m5C differentially expressed regulators, the m5Cscore was constructed, and used to divide patients with BC into high and low m5Cscore groups. Patients with a high m5Cscore had more abundant immune cell infiltration, stronger antitumor immunity, and better prognoses. Finally, Quantitative real-time (PCR) and immunohistochemistry were used for the in vitro experimental validation, which had extensive prognostic value. In this study, we aimed to assess the expression of m5C regulators involved in BC and investigate their correlation with the tumor microenvironment, clinicopathological characteristics, and prognosis of BC. The m5C regulators could be used to effectively assess the cell specific regulation prognosis of patients with BC and develop more effective immunotherapy strategies.
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Affiliation(s)
- Zhe Wang
- Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jinpeng Li
- Department of Obstetrics and Gynecology, Taiyuan People's Hospital, Taiyuan, Shanxi, China
| | - Fucheng Wang
- Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chen Cheng
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xinpei Wu
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wendi Guo
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Chenquan Li
- Department of Breast Surgery, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yinyi Luo
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guangwen Zhang
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sanyuan Zhang
- Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jie Hou
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
| | - Wei Wang
- Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, National Clinical Research Center for Oral Diseases, Shanghai, China.
| | - Shiming Wang
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
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Li P, Huang D. NSUN2-mediated RNA methylation: Molecular mechanisms and clinical relevance in cancer. Cell Signal 2024; 123:111375. [PMID: 39218271 DOI: 10.1016/j.cellsig.2024.111375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
Cancer remains a leading cause of morbidity and mortality worldwide, necessitating the ongoing investigation of molecular targets for improved diagnosis, prognosis, and therapy. Among these targets, RNA modifications, particularly N5-methylcytosine (m5C) in RNA, have emerged as critical regulators of gene expression and cellular functions. NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a key enzyme in m5C modification, significantly influencing various biological processes and tumorigenesis. NSUN2 methylates multiple RNA species, including transfer RNAs (tRNAs), messenger RNAs (mRNAs), and non-coding RNAs, impacting RNA stability, translation efficiency, and cellular stress responses. These modifications, in turn, affect cell proliferation, differentiation, and survival. In cancer, NSUN2 is frequently upregulated, associated with aggressive tumor phenotypes, poor prognosis, and therapy resistance. Its role in oncogenic signaling pathways further underscores its importance in cancer biology. This review offers a comprehensive overview of NSUN2's role in cancer, focusing on its involvement in RNA methylation and its implications for tumor initiation and progression. Additionally, we explore the potential of NSUN2 as a biomarker for cancer diagnosis and prognosis, and its promise as a therapeutic target.
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Affiliation(s)
- Penghui Li
- Department of gastrointestinal surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan, China.
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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Xing H, Gu X, Liu Y, Xu L, He Y, Xue C. NSUN2 regulates Wnt signaling pathway depending on the m5C RNA modification to promote the progression of hepatocellular carcinoma. Oncogene 2024; 43:3469-3482. [PMID: 39375506 DOI: 10.1038/s41388-024-03184-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/26/2024] [Accepted: 09/30/2024] [Indexed: 10/09/2024]
Abstract
5-Methylcytosine (m5C) RNA modification is a highly abundant and important epigenetic modification in mammals. As an important RNA m5C methyltransferase, NOP2/Sun-domain family member 2 (NSUN2)-mediated m5C RNA modification plays an important role in the regulation of the biological functions in many cancers. However, little is known about the biological role of NSUN2 in hepatocellular carcinoma (HCC). In this study, we found that the expression of NSUN2 was significantly upregulated in HCC, and the HCC patients with higher expression of NSUN2 had a poorer prognosis than those with lower expression of NSUN2. NSUN2 could affect the tumor immune regulation of HCC in several ways. In vitro and in vivo experiments confirmed that NSUN2 knockdown significantly decreased the abilities of proliferation, colony formation, migration and invasion of HCC cells. The methylated RNA immunoprecipitation-sequencing (MeRIP-seq) showed NSUN2 knockdown significantly affected the abundance, distribution, and composition of m5C RNA modification in HCC cells. Functional enrichment analyses and in vitro experiments suggested that NSUN2 could promote the HCC cells to proliferate, migrate and invade by regulating Wnt signaling pathway. SARS2 were identified via the RNA immunoprecipitation-sequencing (RIP-Seq) and MeRIP-seq as downstream target of NSUN2, which may play an important role in tumor-promoting effect of NSUN2-mediated m5C RNA modification in HCC. In conclusion, NSUN2 promotes HCC progression by regulating Wnt signaling pathway and SARS2 in an m5C-dependent manner.
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Affiliation(s)
- Huiwu Xing
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
| | - Yingru Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lixia Xu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Chen Xue
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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10
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Li H, Liu H, Zhu D, Dou C, Gang B, Zhang M, Wan Z. Biological function molecular pathways and druggability of DNMT2/TRDMT1. Pharmacol Res 2024; 205:107222. [PMID: 38782147 DOI: 10.1016/j.phrs.2024.107222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024]
Abstract
5-methylcytosine (m5C) is among the most common epigenetic modification in DNA and RNA molecules, and plays an important role in the animal development and disease pathogenesis. Interestingly, unlike other m5C DNA methyltransferases (DNMTs), DNMT2/TRDMT1 has the double-substrate specificity and adopts a DNMT-similar catalytic mechanism to methylate RNA. Moreover, it is widely involved in a variety of physiological regulatory processes, such as the gene expression, precise protein synthesis, immune response, and disease occurrence. Thus, comprehending the epigenetic mechanism and function of DNMT2/TRDMT1 will probably provide new strategies to treat some refractory diseases. Here, we discuss recent studies on the spatiotemporal expression pattern and post-translational modifications of DNMT2/TRDMT1, and summarize the research advances in substrate characteristics, catalytic recognition mechanism, DNMT2/TRDMT1-related genes or proteins, pharmacological application, and inhibitor development. This review will shed light on the pharmacological design by targeting DNMT2/TRDMT1 to treat parasitic, viral and oncologic diseases.
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Affiliation(s)
- Huari Li
- Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, Anhui Province Key Laboratory of Cancer Translational Medicine, and The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu, Anhui Province 233030, PR China; College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan, Hubei Province 430070, PR China.
| | - Huiru Liu
- Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, Anhui Province Key Laboratory of Cancer Translational Medicine, and The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu, Anhui Province 233030, PR China
| | - Daiyun Zhu
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan, Hubei Province 430070, PR China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China
| | - Chengli Dou
- Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, Anhui Province Key Laboratory of Cancer Translational Medicine, and The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu, Anhui Province 233030, PR China
| | - Baocai Gang
- Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, Anhui Province Key Laboratory of Cancer Translational Medicine, and The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu, Anhui Province 233030, PR China
| | - Mengjie Zhang
- Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, Anhui Province Key Laboratory of Cancer Translational Medicine, and The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu, Anhui Province 233030, PR China
| | - Ziyu Wan
- Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, Anhui Province Key Laboratory of Cancer Translational Medicine, and The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu, Anhui Province 233030, PR China
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11
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Qin W, Fei G, Zhou Q, Li Z, Li W, Wei P. Nuclear protein NOP2 serves as a poor-prognosis predictor of LUAD and aggravates the malignancy of lung adenocarcinoma cells. Funct Integr Genomics 2024; 24:58. [PMID: 38489049 DOI: 10.1007/s10142-024-01337-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/29/2024] [Accepted: 03/09/2024] [Indexed: 03/17/2024]
Abstract
Recent studies have shown that NOP2, a nucleolar protein, is up-regulated in various cancers, suggesting a potential link to tumor aggressiveness and unfavorable outcomes. This study examines NOP2's role in lung adenocarcinoma (LUAD), a context where its implications remain unclear. Utilizing bioinformatics, we assessed 513 LUAD and 59 normal tissue samples from The Cancer Genome Atlas (TCGA) to explore NOP2's diagnostic and prognostic significance in LUAD. Additionally, in vitro experiments compared NOP2 expression between Beas-2b and A549 cells. Advanced databases and analytical tools, including LINKEDOMICS, STRING, and TISIDB, were employed to further elucidate NOP2's association with LUAD. Our findings indicate a significantly higher expression of NOP2 mRNA and protein in A549 cells compared to Beas-2b cells (P < 0.001). In LUAD, elevated NOP2 levels were linked to decreased Overall Survival (OS) and advanced clinical stages. Univariate Cox analysis revealed that high NOP2 expression correlated with poorer OS in LUAD (P < 0.01), a finding independently supported by multivariate Cox analysis (P < 0.05). The relationship between NOP2 expression and LUAD risk was presented via a Nomogram. Additionally, Gene Set Enrichment Analysis (GSEA) identified seven NOP2-related signaling pathways. A focal point of our research was the interplay between NOP2 and tumor-immune interactions. Notably, a negative correlation was observed between NOP2 expression and the immune infiltration levels of macrophages, neutrophils, mast cells, Natural Killer (NK) cells, and CD8 + T cells in LUAD. Moreover, the expression of NOP2 was related to the sensitivity of various chemotherapeutic drugs. In vitro, we found that downregulating NOP2 can decrease the proliferation, migration and invasion of A549 cells. Furthermore, NOP2 can regulate Caspase3-mediated apoptosis. Collectively, particularly regarding prognosis, immune infiltration and vitro experiments, these findings suggest NOP2's potential of serving as a poor-prognostic biomarker for LUAD and aggravating the malignancy of lung adenocarcinoma cells.
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Affiliation(s)
- Weizhuo Qin
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing City, 210009, Jiangsu Province, China
| | - Gaoqiang Fei
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing City, 210009, Jiangsu Province, China
| | - Qian Zhou
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing City, 210009, Jiangsu Province, China
| | - Zhijie Li
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing City, 210009, Jiangsu Province, China
| | - Wei Li
- Department of Quality Management, Children's Hospital of Nanjing Medical University, No. 8 Jiangdong South Road, Jianye District, Nanjing City, 210008, Jiangsu Province, China.
| | - Pingmin Wei
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing City, 210009, Jiangsu Province, China.
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12
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Sağlam B, Akgül B. An Overview of Current Detection Methods for RNA Methylation. Int J Mol Sci 2024; 25:3098. [PMID: 38542072 PMCID: PMC10970374 DOI: 10.3390/ijms25063098] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 11/11/2024] Open
Abstract
Epitranscriptomic mechanisms, which constitute an important layer in post-transcriptional gene regulation, are involved in numerous cellular processes under health and disease such as stem cell development or cancer. Among various such mechanisms, RNA methylation is considered to have vital roles in eukaryotes primarily due to its dynamic and reversible nature. There are numerous RNA methylations that include, but are not limited to, 2'-O-dimethyladenosine (m6Am), N7-methylguanosine (m7G), N6-methyladenosine (m6A) and N1-methyladenosine (m1A). These biochemical modifications modulate the fate of RNA by affecting the processes such as translation, target site determination, RNA processing, polyadenylation, splicing, structure, editing and stability. Thus, it is highly important to quantitatively measure the changes in RNA methylation marks to gain insight into cellular processes under health and disease. Although there are complicating challenges in identifying certain methylation marks genome wide, various methods have been developed recently to facilitate the quantitative measurement of methylated RNAs. To this end, the detection methods for RNA methylation can be classified in five categories such as antibody-based, digestion-based, ligation-based, hybridization-based or direct RNA-based methods. In this review, we have aimed to summarize our current understanding of the detection methods for RNA methylation, highlighting their advantages and disadvantages, along with the current challenges in the field.
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Affiliation(s)
| | - Bünyamin Akgül
- Noncoding RNA Laboratory, Department of Molecular Biology and Genetics, İzmir Institute of Technology, Urla, 35430 İzmir, Turkey;
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13
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Zhao Y, Xing C, Peng H. ALYREF (Aly/REF export factor): A potential biomarker for predicting cancer occurrence and therapeutic efficacy. Life Sci 2024; 338:122372. [PMID: 38135116 DOI: 10.1016/j.lfs.2023.122372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/09/2023] [Accepted: 12/18/2023] [Indexed: 12/24/2023]
Abstract
5-Methylcytosine (m5C) methylation is present in almost all types of RNA as an essential epigenetic modification. It is dynamically modulated by its associated enzymes, including m5C methyltransferases (NSUN, DNMT and TRDMT family members), demethylases (TET family and ALKBH1) and binding proteins (YTHDF2, ALYREF and YBX1). Among them, aberrant expression of the RNA-binding protein ALYREF can facilitate a variety of malignant phenotypes such as maintenance of proliferation, malignant heterogeneity, metastasis, and drug resistance to cell death through different regulatory mechanisms, including pre-mRNA processing, mRNA stability, and nuclear-cytoplasmic shuttling. The induction of these cellular processes by ALYREF results in treatment resistance and poor outcomes for patients. However, there are currently few reports of clinical applications or drug trials related to ALYREF. In addition, the looming observations on the role of ALYREF in the mechanisms of carcinogenesis and disease prognosis have triggered considerable interest, but critical evidence is not available. For example, animal experiments and ALYREF small molecule inhibitor trials. In this review, we, therefore, revisit the literature on ALYREF and highlight its importance as a prognostic biomarker for early prevention and as a therapeutic target.
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Affiliation(s)
- Yan Zhao
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Cheng Xing
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Hongling Peng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, Hunan 410011, China; Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan 410011, China.
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14
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Yang S, Zhou D, Zhang C, Xiang J, Xi X. Function of m 5C RNA methyltransferase NOP2 in high-grade serous ovarian cancer. Cancer Biol Ther 2023; 24:2263921. [PMID: 37800580 PMCID: PMC10561575 DOI: 10.1080/15384047.2023.2263921] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/12/2023] [Indexed: 10/07/2023] Open
Abstract
RNA methyltransferase nucleolar protein p120 (NOP2), commonly referred to as NOP2/Sun RNA methyltransferase family member 1 (NSUN1), is involved in cell proliferation and is highly expressed in various cancers. However, its role in high-grade serous ovarian cancer (HGSOC) remains unclear. Our study investigated the expression of NOP2 in HGSOC tissues and normal fimbria tissues, and found that NOP2 was significantly upregulated in HGSOC tissues. Our experiments showed that NOP2 overexpression promoted cell proliferation in vivo and in vitro and increased the migration and invasion ability of HGSOC cells in vitro. Furthermore, we identified Rap guanine nucleotide exchange factor 4 (RAPGEF4) as a potential downstream target of NOP2 in HGSOC. Finally, our findings suggest that the regulation of NOP2 and RAPGEF4 may depend on m5C methylation levels.
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Affiliation(s)
- Shimin Yang
- Department of Gynecology and Obstetrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongmei Zhou
- Department of Gynecology and Obstetrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunxiao Zhang
- Department of Gynecology and Obstetrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiangdong Xiang
- Department of Gynecology and Obstetrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaowei Xi
- Department of Gynecology and Obstetrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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15
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Zheng L, Duan Y, Li M, Wei J, Xue C, Chen S, Wei Q, Tang F, Xiong W, Zhou M, Deng H. Deciphering the vital roles and mechanism of m5C modification on RNA in cancers. Am J Cancer Res 2023; 13:6125-6146. [PMID: 38187052 PMCID: PMC10767349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
5-methylcytosine (m5C modification) plays an essential role in tumors, which affects different types of RNA, the expression of downstream target genes, and downstream pathways, thus participating in the tumor process. However, the effect of m5C modification on RNA in tumors and the exact mechanism have not been systematically reviewed. Therefore, we reviewed the status and sites of m5C modification, as well as the expression pattern and biological functions of m5C regulators in tumors, and further summarized the effects and regulation mechanism of m5C modification on messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), long non-coding RNA (lncRNA) and other RNA in tumors. Finally, we summed up the interaction network, potential application, and value in clinical diagnosis and treatment of tumors. Taken together, this review benefits revealing the mechanism of m5C modification in tumor progression and provides new strategies for tumor diagnosis and treatment.
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Affiliation(s)
- Lemei Zheng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Yumei Duan
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Mengna Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Jianxia Wei
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Changning Xue
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Shipeng Chen
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Qingqing Wei
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Faqing Tang
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Central South UniversityChangsha, Hunan, China
| | - Hongyu Deng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South UniversityChangsha, Hunan, China
- Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha, Hunan, China
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16
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Xiao Z, Li J, Liang C, Liu Y, Zhang Y, Zhang Y, Liu Q, Yan X. Identification of M5c regulator-medicated methylation modification patterns for prognosis and immune microenvironment in glioma. Aging (Albany NY) 2023; 15:12275-12295. [PMID: 37934565 PMCID: PMC10683591 DOI: 10.18632/aging.205179] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 10/02/2023] [Indexed: 11/08/2023]
Abstract
Glioma is a common intracranial tumor and is generally associated with poor prognosis. Recently, numerous studies illustrated the importance of 5-methylcytosine (m5C) RNA modification to tumorigenesis. However, the prognostic value and immune correlation of m5C in glioma remain unclear. We obtained RNA expression and clinical information from The Cancer Genome Atlas (TCGA) and The Chinese Glioma Genome Atlas (CGGA) datasets to analyze. Nonnegative matrix factorization (NMF) was used to classify patients into two subgroups and compare these patients in survival and clinicopathological characteristics. CIBERSORT and single-sample gene-set algorithm (ssGSEA) methods were used to investigate the relationship between m5C and the immune environment. The Weighted correlation network analysis (WGCNA) and univariate Cox proportional hazard model (CoxPH) were used to construct a m5C-related signature. Most of m5C RNA methylation regulators presented differential expression and prognostic values. There were obvious relationships between immune infiltration cells and m5C regulators, especially NSUN7. In the m5C-related module from WGCNA, we found SEPT3, CHI3L1, PLBD1, PHYHIPL, SAMD8, RAP1B, B3GNT5, RER1, PTPN7, SLC39A1, and MXI1 were prognostic factors for glioma, and they were used to construct the signature. The great significance of m5C-related signature in predicting the survival of patients with glioma was confirmed in the validation sets and CGGA cohort.
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Affiliation(s)
- Zhenyong Xiao
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
| | - Jinwei Li
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610000, Sichuan, China
| | - Cong Liang
- Department of Pharmacy, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
| | - Yamei Liu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
| | - Yuxiu Zhang
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
| | - Yuxia Zhang
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
| | - Quan Liu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
| | - Xianlei Yan
- Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, Guangxi, China
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610000, Sichuan, China
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17
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Sun H, Li K, Liu C, Yi C. Regulation and functions of non-m 6A mRNA modifications. Nat Rev Mol Cell Biol 2023; 24:714-731. [PMID: 37369853 DOI: 10.1038/s41580-023-00622-x] [Citation(s) in RCA: 112] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2023] [Indexed: 06/29/2023]
Abstract
Nucleobase modifications are prevalent in eukaryotic mRNA and their discovery has resulted in the emergence of epitranscriptomics as a research field. The most abundant internal (non-cap) mRNA modification is N6-methyladenosine (m6A), the study of which has revolutionized our understanding of post-transcriptional gene regulation. In addition, numerous other mRNA modifications are gaining great attention because of their major roles in RNA metabolism, immunity, development and disease. In this Review, we focus on the regulation and function of non-m6A modifications in eukaryotic mRNA, including pseudouridine (Ψ), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), inosine, 5-methylcytidine (m5C), N4-acetylcytidine (ac4C), 2'-O-methylated nucleotide (Nm) and internal N7-methylguanosine (m7G). We highlight their regulation, distribution, stoichiometry and known roles in mRNA metabolism, such as mRNA stability, translation, splicing and export. We also discuss their biological consequences in physiological and pathological processes. In addition, we cover research techniques to further study the non-m6A mRNA modifications and discuss their potential future applications.
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Affiliation(s)
- Hanxiao Sun
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Kai Li
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Cong Liu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Chengqi Yi
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
- Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
- Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
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Fang Z, Li P, Li F. Combining Bulk RNA-seq and scRNA-seq data to identify RNA m5C methyltransferases NSUN1: a rising star as a biomarker for cancer diagnosis, prognosis and therapy. Transl Cancer Res 2023; 12:2336-2350. [PMID: 37859740 PMCID: PMC10583010 DOI: 10.21037/tcr-23-66] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 07/14/2023] [Indexed: 10/21/2023]
Abstract
Background RNA 5-methylcytosine (m5C) methyltransferases NSUN1 is a member of the NOP2/SUN (NSUN) RNA methyltransferase family. Studies have found that the expression of NSUN1 is elevated in breast and colon cancer and can predict poor prognosis. However, the NSUN1 gene has only been studied in a few tumors. Methods Single-cell RNA sequencing (scRNA-seq) and Bulk RNA-seq data were used for comprehensive analysis of NSUN1 in cancers. The Human Protein Atlas (HPA) database was used to identify the gene location. Immunofluorescence staining was used to detect NSUN1 subcellular distribution within the nucleus, endoplasmic reticulum (ER), and microtubules of A-431, U-2, U-251 cells. The cBioPortal tool was used to analyze the alteration frequency and mutation type. The epigenetic profile of NSUN1 also was analyzed by using the University of Alabama at Birmingham CANcer data analysis Portal (UCLCAN). Tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint expression in cancers were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform enrichment and visualization. The study was based on online resources and public databases. Results Elevated NSUN1 expression had been observed in most human cancers. Analysis of scRNA-seq data showed that NSUN1 was highly expressed in immune cells such as T cells, B cells, and dendritic (DC) cells. High NSUN1 expression indicated poor overall survival (OS) and disease-free survival (DFS). The characteristics of genetic alteration, methylation and phosphorylation of NSUN1 were analyzed and higher levels of phosphorylation in tumor tissues were found. In addition, the expression of NSUN1 was closely related to tumor-infiltrating immune cells. At the same time, the expression of NSUN1 was positively correlated with the expression of multiple immune checkpoints. Conclusions The gene expression profile, survival status, genetic alteration, methylation, phosphorylation and infiltrating immune cells of NSUN1 in human cancers were comprehensively analyzed. The results herein implied that NSUN1 may be an effective biomarker for early cancer diagnosis, prognosis and therapy.
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Affiliation(s)
- Zhen Fang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Peijuan Li
- The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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Zheng L, Li M, Wei J, Chen S, Xue C, Duan Y, Tang F, Li G, Xiong W, She K, Deng H, Zhou M. NOP2/Sun RNA methyltransferase 2 is a potential pan-cancer prognostic biomarker and is related to immunity. PLoS One 2023; 18:e0292212. [PMID: 37769000 PMCID: PMC10538670 DOI: 10.1371/journal.pone.0292212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 09/13/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND NOP2/Sun RNA methyltransferase 2 (NSUN2), an important methyltransferase of m5C, has been poorly studied in cancers, and the relationship between NSUN2 and immunity remains largely unclear. Therefore, the purpose of this study was to explore the expression and prognostic value of NSUN2 and the role of NSUN2 in immunity in cancers. METHODS The TIMER, CPTAC and other databases were used to analyze the expression of NSUN2, its correlation with clinical stage and its prognostic value across cancers. Moreover, the TISIDB, TIMER2.0 and Sangerbox platform were used to depict the relationships between NSUN2 and immune molecular subtypes, tumor-infiltrating lymphocytes (TILs), immune checkpoints (ICPs) and immunoregulatory genes. Furthermore, the NSUN2-interacting proteins and related genes as well as the coexpression networks of NSUN2 in LIHC, LUAD and HNSC were explored with the STRING, DAVID, GEPIA2 and LinkedOmics databases. Finally, the subcellular location and function of NSUN2 in HepG2, A549 and 5-8F cells were investigated by performing immunofluorescence, CCK-8 and wound healing assays. RESULTS Overall, NSUN2 was highly expressed and related to a poor prognosis in most types of cancers and was also significantly associated with immune molecular subtypes in some cancer types. Furthermore, NSUN2 was significantly associated with the levels of ICPs and immunoregulatory genes. In addition, NSUN2 was found to be involved in a series of immune-related biological processes, such as the humoral immune response in LIHC and LUAD and T-cell activation and B-cell activation in HNSC. Immunofluorescence and CCK-8 assays also confirmed that NSUN2 was widely expressed in the nucleus and cytoplasm, and overexpression of NSUN2 promoted the proliferation and migration of HepG2, A549 and 5-8F cells. NSUN2 was also confirmed to positively regulate the expression of PD-L1. CONCLUSION NSUN2 serves as a pan-cancer prognostic biomarker and is correlated with the immune infiltration of tumors.
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Affiliation(s)
- Lemei Zheng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Mengna Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Jianxia Wei
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Shipeng Chen
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Changning Xue
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Yumei Duan
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Faqing Tang
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Kelin She
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- Department of Thoracic Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Hongyu Deng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
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20
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Wang X, Mao Y, Xu H, Chen J, chen X. Identification of m 5C-related molecular subtypes and prediction models in the prognosis and tumor microenvironment infiltration of soft tissue sarcoma. Heliyon 2023; 9:e19680. [PMID: 37809908 PMCID: PMC10558950 DOI: 10.1016/j.heliyon.2023.e19680] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 10/10/2023] Open
Abstract
Background The epigenetic regulator in cancer progression and immune response has been demonstrated recently. However, the potential implications of 5-methylcytosine (m5C) in soft tissue sarcoma (STS) are unclear. Methods The RNA sequence profile of 911 normal and 259 primary STS tissues were obtained from GTEx and TCGA databases, respectively. We systematically analyzed the m5C modification patterns of STS samples based on 11 m5C regulators, and comprehensively correlated these modification patterns with clinical characteristics, prognosis, and tumor microenvironment (TME) cell-infiltrating. Furthermore, an m5C-related signature was generated using Cox proportional hazard model and validated by the GSE17118 cohort. Results Two distinct m5C modification patterns (cluster1/2) were discovered. The cluster1 had favorable overall survival, higher immune score, higher expression of most immune checkpoints, and active immune cell infiltration. The GSVA analysis of the P53 pathway, Wnt signaling pathway, G2M checkpoint, mTORC1 signaling, Wnt/β catenin signaling, and PI3K/AKT/mTOR signaling were significantly enriched in the cluster2. Moreover, 1220 genes were differentially expressed between two clusters, and a m5C prognostic signature was constructed with five m5C-related genes. The signature represented an independent prognostic factor and showed the favorable performance in the GSE17118 cohort. Patients in the low-risk group showed higher immunoscore and higher expression of most immune checkpoints. Further GSVA analysis indicated that the levels of P53 pathway, Wnt signaling pathway, and TGF-β signaling pathway were different between low- and high-risk groups. Moreover, a nomogram incorporating m5C signature and clinical variables was established and showed well performance. Conclusion This work showed that the m5C modification plays a significant role in the progression of STS and the formation of TME diversity. Evaluating the m5C modification pattern of tumor will enhance our cognition of TME infiltration characterization to guide more effective immunotherapy strategies.
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Affiliation(s)
- Xianfeng Wang
- Department of Orthopedics, Suzhou Hospital of Anhui Medical University, Suzhou, 234000, Anhui, China
| | - Yicheng Mao
- Wenzhou Medical University, Wenzhou, 325000, Wenzhou, China
| | - Hanlu Xu
- Wenzhou Medical University, Wenzhou, 325000, Wenzhou, China
| | - Jiyang Chen
- Wenzhou Medical University, Wenzhou, 325000, Wenzhou, China
| | - Xiao chen
- Department of Orthopedics, Suzhou Hospital of Anhui Medical University, Suzhou, 234000, Anhui, China
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21
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Hu S, Yang M, Xiao K, Yang Z, Cai L, Xie Y, Wang L, Wei R. Loss of NSUN6 inhibits osteosarcoma progression by downregulating EEF1A2 expression and activation of Akt/mTOR signaling pathway via m 5C methylation. Exp Ther Med 2023; 26:457. [PMID: 37614424 PMCID: PMC10443047 DOI: 10.3892/etm.2023.12156] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 06/29/2023] [Indexed: 08/25/2023] Open
Abstract
As an important 5-methylcytidine (m5C) methyltransferase, NOP2/Sun RNA methyltransferase family member 6 (NSUN6) has been reported to play an important role in the progression of several diseases. However, the role of NSUN6 in the progression of osteosarcoma (OS) remains unclear. This study aimed to identify the role of NSUN6 in the progression of OS and clarify the potential molecular mechanism. The present study discovered that NSUN6 was upregulated in OS and a higher NSUN6 expression was a strong indicator for poorer prognosis of patients with OS. In addition, the loss of NSUN6 led to reduced proliferation, migration and invasion of OS cells. Through bioinformatics analysis, RNA immunoprecipitation (RIP) and methylated RIP assays, eukaryotic elongation factor 1 α-2 (EEF1A2) was identified and validated as a potential target of NSUN6 in OS. Mechanistically, the expression of EEF1A2 was significantly suppressed following NSUN6 knockdown due to reduced EEF1A2 mRNA stability in an m5C-dependent manner. Meanwhile, NSUN6 deficiency inhibited m5C-dependent activation of Akt/mTOR signaling pathway. In addition, genetic overexpression of EEF1A2 or pharmacological activation of the Akt signaling pathway counteracted the suppressive effects of NSUN6 deficiency on the proliferation, invasion and migration of OS cells. The current findings suggested that NSUN6 may serve as a potential therapeutic target for OS treatment.
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Affiliation(s)
- Sang Hu
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Min Yang
- Department of Orthopedics, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei 434020, P.R. China
| | - Kangwen Xiao
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Zhiqiang Yang
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Lin Cai
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yuanlong Xie
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Linlong Wang
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Renxiong Wei
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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22
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Zhang G, Liu L, Li J, Chen Y, Wang Y, Zhang Y, Dong Z, Xue W, Sun R, Cui G. NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer. Cell Death Discov 2023; 9:219. [PMID: 37393317 DOI: 10.1038/s41420-023-01521-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 07/03/2023] Open
Abstract
NSUN2 is a nuclear RNA methyltransferase which catalyzes 5-methylcytosine (m5C), a posttranscriptional RNA modification. Aberrant m5C modification has been implicated in the development of multiple malignancies. However, its function in pancreatic cancer (PC) needs to be elucidated. Herein, we determined that NSUN2 was overexpressed in PC tissues and related to aggressive clinical features. Silence of NSUN2 by lentivirus weakened the capability of proliferation, migration and invasion of PC cells in vitro and inhibited the growth and metastasis of xenograft tumors in vivo. Contrarily, overexpression of NSUN2 stimulated PC growth and metastasis. Mechanistically, m5C-sequencing (m5C-seq) and RNA-sequencing (RNA-seq) were carried out to identify downstream targets of NSUN2 and results showed that loss of NSUN2 led to decreased m5C modification level concomitant with reduced TIAM2 mRNA expression. Further validation experiments proved that NSUN2 silence accelerated the decay of TIAM2 mRNA in a YBX1-dependent manner. Additionally, NSUN2 exerted its oncogenic function partially through enhancing TIAM2 transcription. More importantly, disruption of the NSUN2/TIAM2 axis repressed the malignant phenotype of PC cells through blocking epithelial-mesenchymal transition (EMT). Collectively, our study highlighted the critical function of NSUN2 in PC and provided novel mechanistic insights into NSUN2/TIAM2 axis as promising therapeutic targets against PC.
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Affiliation(s)
- Guizhen Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Academy of Medical Sciences, Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Liwen Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Academy of Medical Sciences, Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Jianhao Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Yu Chen
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- School of Basic Medical Sciences, Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Yun Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Yize Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Zihui Dong
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China
| | - Wenhua Xue
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P.R. China.
| | - Ranran Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China.
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China.
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China.
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, P. R. China.
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23
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Cusenza VY, Tameni A, Neri A, Frazzi R. The lncRNA epigenetics: The significance of m6A and m5C lncRNA modifications in cancer. Front Oncol 2023; 13:1063636. [PMID: 36969033 PMCID: PMC10033960 DOI: 10.3389/fonc.2023.1063636] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/10/2023] [Indexed: 03/12/2023] Open
Abstract
Most of our transcribed RNAs are represented by non-coding sequences. Long non-coding RNAs (lncRNAs) are transcripts with no or very limited protein coding ability and a length >200nt. They can be epigenetically modified. N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G) and 2’-O-methylation (Nm) are some of the lncRNAs epigenetic modifications. The epigenetic modifications of RNA are controlled by three classes of enzymes, each playing a role in a specific phase of the modification. These enzymes are defined as “writers”, “readers” and “erasers”. m6A and m5C are the most studied epigenetic modifications in RNA. These modifications alter the structure and properties, thus modulating the functions and interactions of lncRNAs. The aberrant expression of several lncRNAs is linked to the development of a variety of cancers and the epigenetic signatures of m6A- or m5C-related lncRNAs are increasingly recognized as potential biomarkers of prognosis, predictors of disease stage and overall survival. In the present manuscript, the most up to date literature is reviewed with the focus on m6A and m5C modifications of lncRNAs and their significance in cancer.
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Affiliation(s)
- Vincenza Ylenia Cusenza
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Annalisa Tameni
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Antonino Neri
- Scientific Directorate, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Raffaele Frazzi
- Scientific Directorate, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
- *Correspondence: Raffaele Frazzi,
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24
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Lin L, Deng C, Zhou C, Zhang X, Zhu J, Liu J, Wu H, He J. NSUN2 gene rs13181449 C>T polymorphism reduces neuroblastoma risk. Gene X 2023; 854:147120. [PMID: 36529349 DOI: 10.1016/j.gene.2022.147120] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/03/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Neuroblastoma is the most common tumor in infants. RNA m5C modification regulates the survival, differentiation, and migration of cells affecting RNA function. However, the effects of the m5C modification methyltransferase gene NSUN2 polymorphism on neuroblastoma susceptibility have not been reported. TaqMan method was used to determine genotypes of four NSUN2 polymorphisms (rs4702373 C>T, rs13181449 C>T, rs166049 T>G, and rs8192120 A>C) in 402 patients with neuroblastoma and 473 cancer-free controls from Jiangsu province, China. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association of NSUN2 polymorphisms with neuroblastoma susceptibility. The association was also further assessed in subgroups stratified by age, sex, tumor origin, and stage. GTEx was used to analyze the effect of these polymorphisms on NSUN2 expression. We found the rs13181449 C>T was significantly associated with reduced neuroblastoma risk (CT vs. CC: adjusted OR = 0.68, 95% CI = 0.51-0.92, P = 0.012; CT/TT vs. CC: adjusted OR = 0.70, 95% CI = 0.53-0.92, P = 0.010). Compared with 0-2 protective genotypes, those with 3-4 protective genotypes could significantly reduce the neuroblastoma risk (adjusted OR = 0.68, 95% CI = 0.52 to 0.90, P = 0.006). Stratification analysis showed that the protective effect of rs13181449 polymorphism remained significant in children with age >18 months, boys, and those with early INSS stages. Moreover, children with more protective genotypes in the same subgroups also exhibited significantly reduced neuroblastoma risk. GTEx analysis showed that the rs13181449 T genotype was related with decreased NSUN2 gene expression. In conclusions, NSUN2 rs13181449 polymorphism is associated with decreased neuroblastoma risk, and the underlying mechanism in neuroblastoma needs further study.
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Affiliation(s)
- Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China
| | - Changmi Deng
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China
| | - Chunlei Zhou
- Department of Pathology, Children's Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu, China
| | - Xinxin Zhang
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China
| | - Jinhong Zhu
- Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
| | - Jiabin Liu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China
| | - Haiyan Wu
- Department of Pathology, Children's Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu, China.
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China.
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25
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Yang WL, Qiu W, Zhang T, Xu K, Gu ZJ, Zhou Y, Xu HJ, Yang ZZ, Shen B, Zhao YL, Zhou Q, Yang Y, Li W, Yang PY, Yang YG. Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis. Nat Commun 2023; 14:863. [PMID: 36792629 PMCID: PMC9932167 DOI: 10.1038/s41467-023-36595-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
T helper 17 (Th17) cells are a subset of CD4+ T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m5C) methyltransferase Nsun2 in mouse CD4+ T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m5C formation and consequently enhanced mRNA stability. Our study demonstrates a m5C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.
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Affiliation(s)
- Wen-Lan Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Weinan Qiu
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.,Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ting Zhang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
| | - Kai Xu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zi-Juan Gu
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Yu Zhou
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Heng-Ji Xu
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhong-Zhou Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University Medical School, 210093, Nanjing, China
| | - Bin Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Yong-Liang Zhao
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Peng-Yuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yun-Gui Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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26
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Tao X, Wu X, Zhou P, Yu X, Zhao C, Peng X, Zhang K, Shen L, Peng J, Yang L. UBE2T promotes glioblastoma malignancy through ubiquitination-mediated degradation of RPL6. Cancer Sci 2023; 114:521-532. [PMID: 36156329 PMCID: PMC9899609 DOI: 10.1111/cas.15604] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 09/16/2022] [Accepted: 09/17/2022] [Indexed: 01/07/2023] Open
Abstract
Glioblastoma (GBM) is the most frequent and aggressive malignant glioma. Due to patients' poor prognosis, it is of great clinical significance to determine new targets that may improve GBM treatment. In the present study, we showed that ubiquitin (Ub)-conjugating enzyme E2T (UBE2T) was significantly overexpressed in GBM and could promote proliferation, invasion, and inhibit apoptosis of GBM cells. Mechanistically, UBE2T functioned as the Ub enzyme of ribosomal protein L6 (RPL6) and induced the ubiquitination and degradation of RPL6 in an E3 ligase-independent manner through direct modification by K48-linked polyubiquitination, thus contributing to the malignant progression of GBM cells. Furthermore, inhibiting the expression of RPL6 by UBE2T could not only reduce the expression of wild-type p53, but also enhance the gain-of-function of mutant p53. Moreover, knockdown of UBE2T in LN229 cells obviously suppressed tumor growth in LN229 xenograft mouse models. Collectively, our study demonstrated that UBE2T promotes GBM malignancy through ubiquitination-mediated degradation of RPL6 regardless of the p53 mutation status. It will provide new candidates for molecular biomarkers and therapeutic targets for clinical application in GBM.
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Affiliation(s)
- Xuxiu Tao
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
| | - Xia Wu
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
- Department of PathologyThe Second Xiangya Hospital, Central South UniversityChangshaChina
| | - Peijun Zhou
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
| | - Xuehui Yu
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
| | - Chen Zhao
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
| | - Xingzhi Peng
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
| | - Kun Zhang
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
| | - Liangfang Shen
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
| | - Jinwu Peng
- Department of PathologyXiangya Hospital, Central South UniversityChangshaChina
- Department of PathologyXiangya Changde HospitalChangdeChina
| | - Lifang Yang
- Department of OncologyKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaChina
- Cancer Research Institute, School of Basic Medicine Science, Central South UniversityChangshaChina
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Zhang L, Zhang Y, Zhang S, Qiu L, Zhang Y, Zhou Y, Han J, Xie J. Translational Regulation by eIFs and RNA Modifications in Cancer. Genes (Basel) 2022; 13:2050. [PMID: 36360287 PMCID: PMC9690228 DOI: 10.3390/genes13112050] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/25/2022] [Accepted: 11/04/2022] [Indexed: 11/04/2023] Open
Abstract
Translation is a fundamental process in all living organisms that involves the decoding of genetic information in mRNA by ribosomes and translation factors. The dysregulation of mRNA translation is a common feature of tumorigenesis. Protein expression reflects the total outcome of multiple regulatory mechanisms that change the metabolism of mRNA pathways from synthesis to degradation. Accumulated evidence has clarified the role of an increasing amount of mRNA modifications at each phase of the pathway, resulting in translational output. Translation machinery is directly affected by mRNA modifications, influencing translation initiation, elongation, and termination or altering mRNA abundance and subcellular localization. In this review, we focus on the translation initiation factors associated with cancer as well as several important RNA modifications, for which we describe their association with cancer.
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Affiliation(s)
- Linzhu Zhang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- The Third People’s Hospital of Chengdu, Clinical College of Southwest Jiao Tong University, Chengdu 610014, China
| | - Yaguang Zhang
- State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Su Zhang
- State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lei Qiu
- State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yang Zhang
- State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ying Zhou
- State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Junhong Han
- State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiang Xie
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- The Third People’s Hospital of Chengdu, Clinical College of Southwest Jiao Tong University, Chengdu 610014, China
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Sun G, Ma S, Zheng Z, Wang X, Chen S, Chang T, Liang Z, Jiang Y, Xu S, Liu R. Multi-omics analysis of expression and prognostic value of NSUN members in prostate cancer. Front Oncol 2022; 12:965571. [PMID: 35978830 PMCID: PMC9376292 DOI: 10.3389/fonc.2022.965571] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/07/2022] [Indexed: 11/30/2022] Open
Abstract
Background Prostate cancer is the most common tumor in men worldwide, seriously threatening the health of older men, and 5-methylcytosine (m5C) RNA modification has been shown to have a significant impact on the development and progression of various tumors. However, as the most critical methyltransferase for m5c RNA modification, the role of the NSUN members (NSUN1-7) in prostate cancer is unclear. Methods We obtained sequencing data of genes and related clinical data of prostate cancer from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database and analyzed the correlation between NSUN members’ expression and prognosis. we found that NSUN2 was closely implicated in the prognosis of prostate cancer, then verified the expression of NSUN2 in clinical samples, and obtained the correlation between NSUN2 and immune cell infiltration through CIBERSORT algorithm and ESTIMATE method. The relationship between NSUN2 copy number variation and immune cell infiltration was further analyzed in the TIMER database and identified signaling pathways associated with NSUN2 expression by GO, KEGG, and GSEA analysis. Finally, we verified the expression of NSUN2 in prostate cancer cell lines and confirmed the role of NSUN2 on the biological behavior of prostate cancer cells by proliferation and migration-related assays. Results NOP2 and NSUN2 were upregulated in prostate tumor tissues. NSUN2 expression is closely associated with tumor prognosis. NSUN2 high expression implies poor clinical features, and the NSUN family is significantly associated with tumor stromal score and immune score. Besides, NSUN2 is associated with a variety of immune infiltrating cells (B cells memory, T cells CD4 memory resting, T cells CD4 memory activated, NK cells resting, and so on). High NSUN2 expression lowers the sensitivity of many chemotherapy drugs, such as docetaxel, doxorubicin, fluorouracil, cisplatin, and etoposide. In prostate cancer, the most common type of mutation in NSUN2 is amplification, and NSUN2 copy number variation is closely associated with NSUN2 expression and immune cell infiltration. GSEA analysis showed that the related genes were mainly enriched in ubiquitin-mediated protein hydrolysis, cell cycle, RNA degradation, endometrial cancer, prostate cancer, p53 signaling pathway, and NSUN2 potentiated the proliferation and migration of prostate cancer cells. Conclusions NSUN2 is highly expressed in prostate cancer, which contributes to the progression of prostate cancer, and is closely implicated in immune cell infiltration and chemotherapy drugs. NSUN2 is expected to be a prospective marker and a new treatment target for prostate cancer.
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Pan Q, Yi C, Zhang Y. Overall Survival Signature of 5-Methylcytosine Regulators Related Long Non-Coding RNA in Hepatocellular Carcinoma. Front Oncol 2022; 12:884377. [PMID: 35686101 PMCID: PMC9172585 DOI: 10.3389/fonc.2022.884377] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/08/2022] [Indexed: 12/28/2022] Open
Abstract
Purpose Studies reported that 5-methylcytosine (m5C) RNA transferase alters tumor progression; however, studies of m5C-related lncRNA remain lacking. This article intends to study the lncRNA modified by m5C RNA transferase in hepatocellular carcinoma using a combination of computational biology and basic experiments. Method We identified 13 m5C RNA transferase-related genes and selected long non-coding RNAs with a Pearson correlation coefficient greater than 0.4. Univariate Cox regression analysis was used to screen m5C RNA transferase lncRNA related to survival phenotype. We divided TCGA-LIHC into two types of m5C RNA using non-negative matrix decomposition. According to WGCNA, the co-expression models of two lncRNA regulation modes were constructed to analyze the characteristic biological processes of the two m5C RNA transferase-related lncRNA gene models. Then, a predictive model of m5C RNA transferase lncRNA was using LASSO regression. Finally, we used cell experiments, transwell experiments, and clone formation experiments to test the relationship between SNHG4 and tumor cell proliferation in Hep-G2 and Hep-3b cells line. Results We identified 436 m5C RNA transferase-related lncRNAs. Using univariate Cox regression analysis, 43 prognostic-related lncRNAs were determined according to P < 0.001. We divided TCGA-LIHC into two regulation modes of m5C RNA transferase using non-negative matrix factorization. The two regulation modes showed significant differences in overall and disease-free survival. We used LASSO to construct m5c-related lncRNA prognostic signature. Thus, a predictive m5C-lncRNA model was established using four lncRNAs: AC026412.3, AC010969.2, SNHG4, and AP003392.5. The score calculated by the m5C-lncRNA model significantly correlated with the overall survival of hepatocellular carcinoma. The receiver operating characteristic curve and decision curve analysis verified the accuracy of the predictive model. We observed a more robust immune response in the high-risk score group. The transwell experiments and clone formation experiments suggested that m5C RNA transferase-related lncRNA SNHG4 promotes the proliferation and migration of Hep-G2 and Hep-3b cells line. Conclusion Two lncRNA expression patterns regulated by m5C RNA transferase were identified. The difference between the two expression patterns and the survival phenotype in the biological process was pointed out. A 5-methylcytosine RNA methyltransferases-related lncRNA overall survival signature was constructed. These results provide some understanding of the influence of m5C transferase on hepatocellular carcinoma. The prediction model of m5C transferase lncRNA has potential clinical value in managing hepatocellular carcinoma.
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Affiliation(s)
- Qi Pan
- Key Laboratory of Organ Transplantation of Liaoning Province, Department of Hepatobiliary Surgery and Organ Transplantation, First Hospital of China Medical University, Shenyang, China
| | - Caiyu Yi
- China Medical University, Shenyang, China
| | - Yijie Zhang
- Key Laboratory of Organ Transplantation of Liaoning Province, Department of Hepatobiliary Surgery and Organ Transplantation, First Hospital of China Medical University, Shenyang, China
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Li M, Tao Z, Zhao Y, Li L, Zheng J, Li Z, Chen X. 5-methylcytosine RNA methyltransferases and their potential roles in cancer. J Transl Med 2022; 20:214. [PMID: 35562754 PMCID: PMC9102922 DOI: 10.1186/s12967-022-03427-2] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/05/2022] [Indexed: 12/28/2022] Open
Abstract
In recent years, 5-methylcytosine (m5C) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs. Accumulating evidence has shown that m5C modulates the stability, translation, transcription, nuclear export, and cleavage of RNAs to mediate cell proliferation, differentiation, apoptosis, stress responses, and other biological functions. In humans, m5C RNA modification is catalyzed by the NOL1/NOP2/sun (NSUN) family and DNA methyltransferase 2 (DNMT2). These RNA modifiers regulate the expression of multiple oncogenes such as fizzy-related-1, forkhead box protein C2, Grb associated-binding protein 2, and TEA domain transcription factor 1, facilitating the pathogenesis and progression of cancers. Furthermore, the aberrant expression of methyltransferases have been identified in various cancers and used to predict the prognosis of patients. In this review, we present a comprehensive overview of m5C RNA methyltransferases. We specifically highlight the potential mechanism of action of m5C in cancer. Finally, we discuss the prospect of m5C-relative studies.
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Affiliation(s)
- Mingyang Li
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Zijia Tao
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Yiqiao Zhao
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Lei Li
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Jianyi Zheng
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Zeyu Li
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Xiaonan Chen
- Department of Urology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China.
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Bai M, Sun C. M5C-Related lncRNA Predicts Lung Adenocarcinoma and Tumor Microenvironment Remodeling: Computational Biology and Basic Science. Front Cell Dev Biol 2022; 10:885568. [PMID: 35592248 PMCID: PMC9110831 DOI: 10.3389/fcell.2022.885568] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/18/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose: Epigenetic RNA modification regulates gene expression post-transcriptionally. The aim of this study was to construct a prognostic risk model for lung adenocarcinoma (LUAD) using long non-coding RNAs (lncRNAs) related to m5C RNA methylation. Method: The lncRNAs regulated by m5C methyltransferase were identified in TCGA-LUAD dataset using Pearson correlation analysis (coefficient > 0.4), and clustered using non-negative matrix decomposition. The co-expressing gene modules were identified by WGCNA and functionally annotated. The prognostically relevant lncRNAs were screened by LASSO regression and a risk model was constructed. LINC00628 was silenced in the NCI-H460 and NCI-H1299 cell lines using siRNA constructs, and migration and invasion were assessed by the Transwell and wound healing assays respectively. Results: We identified 185 m5C methyltransferase-related lncRNAs in LUAD, of which 16 were significantly associated with overall survival. The lncRNAs were grouped into two clusters on the basis of m5C pattern, and were associated with significant differences in overall and disease-free survival. GSVA revealed a close relationship among m5C score, ribosomes, endolysosomes and lymphocyte migration. Using LASSO regression, we constructed a prognostic signature consisting of LINC00628, LINC02147, and MIR34AHG. The m5C-lncRNA signature score was closely related to overall survival, and the accuracy of the predictive model was verified by the receiver operating characteristic curve and decision curve analysis. Knocking down LINC00628 in NCI-H460 and NCI-H1299 cells significantly reduced their migration and invasion compared to that of control cells. Conclusion: We constructed a prognostic risk model of LUAD using three lncRNAs regulated by m5C methyltransferase, which has potential clinical value.
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Affiliation(s)
- Ming Bai
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
| | - Chen Sun
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
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Chen SY, Chen KL, Ding LY, Yu CH, Wu HY, Chou YY, Chang CJ, Chang CH, Wu YN, Wu SR, Hou YC, Lee CT, Chen PC, Shan YS, Huang PH. RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer. Oncogene 2022; 41:3162-3176. [PMID: 35501460 DOI: 10.1038/s41388-022-02325-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 03/26/2022] [Accepted: 04/14/2022] [Indexed: 11/09/2022]
Abstract
Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m5C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m5C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m5C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the LSL-KrasG12D/+;Trp53fl/fl;Pdx1-Cre (KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant KrasG12D and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo. SIGNIFICANCE: Transcriptome-wide mRNA bisulfite sequencing identified candidate m5C sites of mRNAs in human pancreatic cancer cells. NSUN2-mediated m5C mRNA metabolism was observed in a mouse model of pancreatic cancer. NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation.
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Affiliation(s)
- Szu-Ying Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuan-Lin Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Li-Yun Ding
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Hung Yu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsin-Yi Wu
- Instrumentation Center, College of Science, National Taiwan University, Tainan, Taiwan
| | - Ya-Yi Chou
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Jung Chang
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Han Chang
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan
- Center for Corporate Relations and Technology Transfer, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Na Wu
- International Institute for Macromolecular Analysis and Nanomedicine Innovations, Tainan, Taiwan
| | - Shang-Rung Wu
- International Institute for Macromolecular Analysis and Nanomedicine Innovations, Tainan, Taiwan
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Chin Hou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Ta Lee
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Peng-Chieh Chen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Po-Hsien Huang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Tong X, Xiang Y, Hu Y, Hu Y, Li H, Wang H, Zhao KN, Xue X, Zhu S. NSUN2 Promotes Tumor Progression and Regulates Immune Infiltration in Nasopharyngeal Carcinoma. Front Oncol 2022; 12:788801. [PMID: 35574373 PMCID: PMC9099203 DOI: 10.3389/fonc.2022.788801] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 03/31/2022] [Indexed: 12/22/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in the head and neck with a complex etiology, such as environmental factors, genetic factors, and Epstein-Barr virus infection. The NOP2/Sun domain family, member 2 (NSUN2) is a methyltransferase of m5C methylation modification that has been reported to be involved in the occurrence and progression of various tumors, but its role in NPC remains unclear. In this study, we found that NSUN2 was upregulated in NPC and predicted a poor prognosis for NPC patients in both GEO datasets and our tissue microarrays containing 125 NPC tissues. Next, we demonstrated that NSUN2 promoted the proliferation, migration, and invasion of NPC cells in vitro. Additionally, the differential expression genes between NSUN2-high and low expression patients were mainly enriched in multi-immune cell activation and proliferation. Furthermore, NSUN2 negatively regulates immune cell infiltration in the tumor microenvironment (TME) of NPC, which indicates that the NSUN2 level may be negatively correlated with the sensitivity of immunotherapy and chemotherapy. In conclusion, our findings highlight that NSUN2 might act as an important oncogene involved in NPC progression and serve as a potential biomarker to predict poor prognosis and drug sensitivity of NPC patients.
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Affiliation(s)
- Xinya Tong
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yilan Xiang
- Department of Radiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuanbo Hu
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
- Department of Gastrointestinal Surgery, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yingying Hu
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - He Li
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huilin Wang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Kong-Nan Zhao
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shanli Zhu
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
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Role of main RNA modifications in cancer: N 6-methyladenosine, 5-methylcytosine, and pseudouridine. Signal Transduct Target Ther 2022; 7:142. [PMID: 35484099 PMCID: PMC9051163 DOI: 10.1038/s41392-022-01003-0] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022] Open
Abstract
Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.
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Song D, Shyh-Chang N. An RNA methylation code to regulate protein translation and cell fate. Cell Prolif 2022; 55:e13224. [PMID: 35355346 PMCID: PMC9136488 DOI: 10.1111/cpr.13224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/28/2022] [Accepted: 03/06/2022] [Indexed: 11/28/2022] Open
Affiliation(s)
- Dan Song
- State Key Laboratory of Stem Cell and Reproductive Biology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Ng Shyh-Chang
- State Key Laboratory of Stem Cell and Reproductive Biology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
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Liu Y, Zheng S, Wang T, Fang Z, Kong J, Liu J. Identification of the Expression Patterns and Potential Prognostic Role of 5-Methylcytosine Regulators in Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:842220. [PMID: 35252205 PMCID: PMC8888979 DOI: 10.3389/fcell.2022.842220] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/28/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis. 5-methylcytosine (m5C) modification plays a nonnegligible role in tumor pathogenesis and progression. However, little is known about the role of m5C regulators in HCC. Methods: Based on 9 m5C regulators, the m5C modification patterns of HCC samples extracted from public databases were systematically evaluated and correlated with tumor immune and prognosis characteristics. An integrated model called the “m5Cscore” was constructed using principal component analysis, and its prognostic value was evaluated. Results: Almost all m5C regulators were differentially expressed between HCC and normal tissues. Through unsupervised clustering, three different m5Cclusters were ultimately uncovered; these clusters were characterized by differences in prognosis, immune cell infiltration, and pathway signatures. The m5Cscore was constructed to quantify the m5C modifications of individual patients. Subsequent analysis revealed that the m5Cscore was an independent prognostic factor of HCC and could be a novel indicator to predict the prognosis of HCC. Conclusion: This study comprehensively explored and systematically profiled the features of m5C modification in HCC. m5C modification patterns play a crucial role in the tumor immune microenvironment (TIME) and prognosis of HCC. The m5Cscore provides a more holistic understanding of m5C modification in HCC and provides a practical tool for predicting the prognosis of HCC. This study will help clinicians identify effective indicators of HCC to improve the poor prognosis of this disease.
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Affiliation(s)
- Yong Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shunzhen Zheng
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tao Wang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ziqi Fang
- Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Junjie Kong
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Signature of m5C-Related lncRNA for Prognostic Prediction and Immune Responses in Pancreatic Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7467797. [PMID: 35211172 PMCID: PMC8863480 DOI: 10.1155/2022/7467797] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/15/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) has a high mortality and dismal prognosis, predicting to be the second most lethal malignancy. 5-Methylcytosine (m5C) and long noncoding RNAs (lncRNAs) are both crucial in the prognostic outcome and immunotherapeutic effect for PC patients. Therefore, we aimed to create an m5C-related lncRNA signature (m5C-LS) for PC patients' prognosis and treatment. METHODS Clinicopathological information and RNAseq data were acquired from The Cancer Genome Atlas (TCGA) database. Pearson's correlation analysis was used to extract m5C-related lncRNAs in PC. Univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were adopted to build an m5C-LS. Kaplan-Meier (K-M), principal component analysis (PCA), and nomogram were utilized to assess model accuracy. In addition, we explored the model's possible immunotherapeutic responses and drug sensitivity targets. RESULTS Three m5C-related lncRNAs were finally established to construct the risk signature, which has a good and independent predictive ability for PC patients. Based on the m5C-LS, patients were classified into the low- and high-m5C-LS group, with the latter having a worse prognosis. Furthermore, the m5C-LS allowed us to better discriminate the immunotherapeutic responses of PC patients in different subgroups. CONCLUSIONS Our study constructed an m5C-LS and established a nomogram model that accurately predicted the prognosis of PC patients, as well as provides promising immunotherapeutic strategies in the future.
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Wang L, Zhang J, Su Y, Maimaitiyiming Y, Yang S, Shen Z, Lin S, Shen S, Zhan G, Wang F, Hsu CH, Cheng X. Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers. Front Oncol 2022; 12:786266. [PMID: 35280737 PMCID: PMC8916577 DOI: 10.3389/fonc.2022.786266] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 01/24/2022] [Indexed: 01/01/2023] Open
Abstract
RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women’s reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.
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Affiliation(s)
- Lingfang Wang
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Women’s Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Zhang
- Women’s Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yingfeng Su
- Women’s Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yasen Maimaitiyiming
- Women’s Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Hematology of First Affiliated Hospital and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Siqi Yang
- Department of Clinical Research Center, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhangjin Shen
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shitong Lin
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shizhen Shen
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guankai Zhan
- Women’s Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Fenfen Wang
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chih-Hung Hsu
- Women’s Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Chih-Hung Hsu, ; Xiaodong Cheng,
| | - Xiaodong Cheng
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Chih-Hung Hsu, ; Xiaodong Cheng,
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Huang Y, Huang C, Jiang X, Yan Y, Zhuang K, Liu F, Li P, Wen Y. Exploration of Potential Roles of m5C-Related Regulators in Colon Adenocarcinoma Prognosis. Front Genet 2022; 13:816173. [PMID: 35281843 PMCID: PMC8908034 DOI: 10.3389/fgene.2022.816173] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value. Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database. Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified. Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.
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Affiliation(s)
- Yuancheng Huang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chaoyuan Huang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaotao Jiang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanhua Yan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kunhai Zhuang
- Department of Gastroenterology, Baiyun Branch of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengbin Liu
- Department of Gastroenterology, Baiyun Branch of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
| | - Peiwu Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
| | - Yi Wen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
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40
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Wang K, Zhong W, Long Z, Guo Y, Zhong C, Yang T, Wang S, Lai H, Lu J, Zheng P, Mao X. 5-Methylcytosine RNA Methyltransferases-Related Long Non-coding RNA to Develop and Validate Biochemical Recurrence Signature in Prostate Cancer. Front Mol Biosci 2021; 8:775304. [PMID: 34926580 PMCID: PMC8672116 DOI: 10.3389/fmolb.2021.775304] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/01/2021] [Indexed: 02/02/2023] Open
Abstract
The effects of 5-methylcytosine in RNA (m5C) in various human cancers have been increasingly studied recently; however, the m5C regulator signature in prostate cancer (PCa) has not been well established yet. In this study, we identified and characterized a series of m5C-related long non-coding RNAs (lncRNAs) in PCa. Univariate Cox regression analysis and least absolute shrinkage and selector operation (LASSO) regression analysis were implemented to construct a m5C-related lncRNA prognostic signature. Consequently, a prognostic m5C-lnc model was established, including 17 lncRNAs: MAFG-AS1, AC012510.1, AC012065.3, AL117332.1, AC132192.2, AP001160.2, AC129510.1, AC084018.2, UBXN10-AS1, AC138956.2, ZNF32-AS2, AC017100.1, AC004943.2, SP2-AS1, Z93930.2, AP001486.2, and LINC01135. The high m5C-lnc score calculated by the model significantly relates to poor biochemical recurrence (BCR)-free survival (p < 0.0001). Receiver operating characteristic (ROC) curves and a decision curve analysis (DCA) further validated the accuracy of the prognostic model. Subsequently, a predictive nomogram combining the prognostic model with clinical features was created, and it exhibited promising predictive efficacy for BCR risk stratification. Next, the competing endogenous RNA (ceRNA) network and lncRNA–protein interaction network were established to explore the potential functions of these 17 lncRNAs mechanically. In addition, functional enrichment analysis revealed that these lncRNAs are involved in many cellular metabolic pathways. Lastly, MAFG-AS1 was selected for experimental validation; it was upregulated in PCa and probably promoted PCa proliferation and invasion in vitro. These results offer some insights into the m5C's effects on PCa and reveal a predictive model with the potential clinical value to improve the prognosis of patients with PCa.
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Affiliation(s)
- Ke Wang
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Urology, The Hospital of Trade-Business in Hunan Province, Changsha, China
| | - Weibo Zhong
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zining Long
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yufei Guo
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chuanfan Zhong
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Taowei Yang
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shuo Wang
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Houhua Lai
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jianming Lu
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Pengxiang Zheng
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Urology, Fuqing City Hospital Affiliated with Fujian Medical University, Fuzhou, China
| | - Xiangming Mao
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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tRNA modifications and their potential roles in pancreatic cancer. Arch Biochem Biophys 2021; 714:109083. [PMID: 34785212 DOI: 10.1016/j.abb.2021.109083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/05/2021] [Accepted: 11/06/2021] [Indexed: 12/23/2022]
Abstract
Since the breakthrough discovery of N6-methyladenosine (m6A), the field of RNA epitranscriptomics has attracted increasing interest in the biological sciences. Transfer RNAs (tRNAs) are extensively modified, and various modifications play a crucial role in the formation and stability of tRNA, which is universally required for accurate and efficient functioning of tRNA. Abnormal tRNA modification can lead to tRNA degradation or specific cleavage of tRNA into fragmented derivatives, thus affecting the translation process and frequently accompanying a variety of human diseases. Increasing evidence suggests that tRNA modification pathways are also misregulated in human cancers. In this review, we summarize tRNA modifications and their biological functions, describe the type and frequency of tRNA modification alterations in cancer, and highlight variations in tRNA-modifying enzymes and the multiple functions that they regulate in different types of cancers. Furthermore, the current implications and the potential role of tRNA modifications in the progression of pancreatic cancer are discussed. Collectively, this review describes recent advances in tRNA modification in cancers and its potential significance in pancreatic cancer. Further study of the mechanism of tRNA modifications in pancreatic cancer may provide possibilities for therapies targeting enzymes responsible for regulating tRNA modifications in pancreatic cancer.
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Guo G, Pan K, Fang S, Ye L, Tong X, Wang Z, Xue X, Zhang H. Advances in mRNA 5-methylcytosine modifications: Detection, effectors, biological functions, and clinical relevance. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:575-593. [PMID: 34631286 PMCID: PMC8479277 DOI: 10.1016/j.omtn.2021.08.020] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
5-methylcytosine (m5C) post-transcriptional modifications affect the maturation, stability, and translation of the mRNA molecule. These modifications play an important role in many physiological and pathological processes, including stress response, tumorigenesis, tumor cell migration, embryogenesis, and viral replication. Recently, there has been a better understanding of the biological implications of m5C modification owing to the rapid development and optimization of detection technologies, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA-BisSeq. Further, predictive models (such as PEA-m5C, m5C-PseDNC, and DeepMRMP) for the identification of potential m5C modification sites have also emerged. In this review, we summarize the current experimental detection methods and predictive models for mRNA m5C modifications, focusing on their advantages and limitations. We systematically surveyed the latest research on the effectors related to mRNA m5C modifications and their biological functions in multiple species. Finally, we discuss the physiological effects and pathological significance of m5C modifications in multiple diseases, as well as their therapeutic potential, thereby providing new perspectives for disease treatment and prognosis.
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Affiliation(s)
- Gangqiang Guo
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Kan Pan
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Su Fang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lele Ye
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinya Tong
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhibin Wang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huidi Zhang
- Department of Nephrology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Zhai CT, Tian YC, Tang ZX, Shao LJ. RNA methyltransferase NSUN2 promotes growth of hepatocellular carcinoma cells by regulating fizzy-related-1 in vitro and in vivo. Kaohsiung J Med Sci 2021; 37:991-999. [PMID: 34370374 DOI: 10.1002/kjm2.12430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/16/2021] [Accepted: 06/20/2021] [Indexed: 12/29/2022] Open
Abstract
The aim of the study was to investigate the role of NSUN2 (NOP2/Sun RNA Methyltransferase Family Member 2) in hepatocellular carcinoma (HCC). The expressions of NSUN2 and FZR1 were measured. Cell viability, proliferation, and apoptosis were assessed. HCC xenograft in nude mouse model was established. Tumor weight and volume were examined. Tumor tissues were collected for immunohistochemistry (IHC). TCGA database analysis and clinical sample testing suggested that the transcript levels of NSUN2 and FZR1 were increased in HCC tissues. NSUN2 knockdown inhibited HCC cell viability and proliferation, and promoted cell apoptosis. Moreover, the effects of NSUN2 could be countered by overexpressing FZR1. In animal experiment, NSUN2 silencing suppressed tumor growth in nude mice by downregulating FZR1. In conclusion, NSUN2 has a regulatory effect on HCC cell proliferation and apoptosis. NSUN2 knockout could inhibit cellular processes in HCC and tumor growth, likely via FZR1 inhibition. This finding has not only revealed the role of NSUN2 in HCC growth, but also suggests a promising target for HCC treatment.
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Affiliation(s)
- Chun-Tao Zhai
- Department of General Surgery, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medcial University, Jiangsu Province, China
| | - Yi-Cheng Tian
- Department of General Surgery, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medcial University, Jiangsu Province, China
| | - Zu-Xiong Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Jiangsu Province, China
| | - Long-Jiang Shao
- Department of General Surgery, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medcial University, Jiangsu Province, China
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Li J, Zuo Z, Lai S, Zheng Z, Liu B, Wei Y, Han T. Differential analysis of RNA methylation regulators in gastric cancer based on TCGA data set and construction of a prognostic model. J Gastrointest Oncol 2021; 12:1384-1397. [PMID: 34532096 DOI: 10.21037/jgo-21-325] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/02/2021] [Indexed: 12/29/2022] Open
Abstract
Background Methylation is one of the common forms of RNA modification, which mainly include N6-methyladenosine (m6A), C5-methylcytidine (m5C), and N1-methyladenosine (m1A). Numerous studies have shown that RNA methylation is associated with tumor development. We aim to construct prognostic models of gastric cancer based on RNA methylation regulators. Methods The transcriptome and clinical data of gastric cancer and normal samples were obtained from the National Cancer Institute Genome Data Commons (NCI-GDC). Use Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis to construct risk models for different types of RNA methylation. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive efficiency of risk characteristics. Cluster heat maps are used to assess the correlation with clinical information. Univariate and multivariate Cox analyses were used to analyze prognostic effects of risk scores. Gene Set Enrichment Analysis (GSEA) analyzes the functional enrichment of RNA methylation genes. And make a separate analysis of the data of Asians. Results The expression of most of the 30 RNA methylation regulators were significantly different in cancer and paracancerous tissues (P<0.05). Three methylated genes (FTO, ALKBH5, and RBM15) were screened from m6A by LASSO Cox regression analysis. Five methylated genes (FTO, ALKBH5, TRMT61B, RBM15, and YXB1) were selected from the population, and were used to construct two risk ratio models. Survival analysis showed that the survival rate of patients in the low-risk group was significantly higher than that in the high-risk group (P<0.05). All ROC curves indicated that the predictive efficiency of risk characteristics was good [area under the ROC curve (AUC): 0.6-1].Cluster analysis reveals differences in clinical data between the two groups. Univariate and multivariate Cox regression results show that the risk score has independent prognostic value. GSEA showed that pathways such as cell cycle were significantly enriched in the low-risk group, while pathways such as calcium signaling pathway were significantly enriched in the high-risk group. In addition, three methylation models that can predict the prognosis of Asian gastric cancer patients were obtained. Conclusions The methylation prognosis model constructed in this study can effectively predict the prognosis of gastric cancer patients.
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Affiliation(s)
- Jing Li
- Key Laboratory of Visceral Theory and Application in Traditional Chinese Medicine of Ministry of Education, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Zhifan Zuo
- China Medical University, The General Hospital of Northern Theater Command Training Base for Graduate, Shenyang, China
| | - Shusheng Lai
- Department of Medical Imaging, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhendong Zheng
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, China
| | - Bo Liu
- Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuan Wei
- Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Tao Han
- Key Laboratory of Visceral Theory and Application in Traditional Chinese Medicine of Ministry of Education, Liaoning University of Traditional Chinese Medicine, Shenyang, China.,Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang, China
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Zhang Q, Liu F, Chen W, Miao H, Liang H, Liao Z, Zhang Z, Zhang B. The role of RNA m 5C modification in cancer metastasis. Int J Biol Sci 2021; 17:3369-3380. [PMID: 34512153 PMCID: PMC8416729 DOI: 10.7150/ijbs.61439] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/19/2021] [Indexed: 12/26/2022] Open
Abstract
Epigenetic modification plays a crucial regulatory role in the biological processes of eukaryotic cells. The recent characterization of DNA and RNA methylation is still ongoing. Tumor metastasis has long been an unconquerable feature in the fight against cancer. As an inevitable component of the epigenetic regulatory network, 5-methylcytosine is associated with multifarious cellular processes and systemic diseases, including cell migration and cancer metastasis. Recently, gratifying progress has been achieved in determining the molecular interactions between m5C writers (DNMTs and NSUNs), demethylases (TETs), readers (YTHDF2, ALYREF and YBX1) and RNAs. However, the underlying mechanism of RNA m5C methylation in cell mobility and metastasis remains unclear. The functions of m5C writers and readers are believed to regulate gene expression at the post-transcription level and are involved in cellular metabolism and movement. In this review, we emphatically summarize the recent updates on m5C components and related regulatory networks. The content will be focused on writers and readers of the RNA m5C modification and potential mechanisms in diseases. We will discuss relevant upstream and downstream interacting molecules and their associations with cell migration and metastasis.
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Affiliation(s)
- Qiaofeng Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wei Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Hongrui Miao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei 430030, China.,Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
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Hu Y, Chen C, Tong X, Chen S, Hu X, Pan B, Sun X, Chen Z, Shi X, Hu Y, Shen X, Xue X, Lu M. NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation. Cell Death Dis 2021; 12:842. [PMID: 34504059 PMCID: PMC8429414 DOI: 10.1038/s41419-021-04127-3] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 08/08/2021] [Accepted: 08/23/2021] [Indexed: 12/16/2022]
Abstract
The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.
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Affiliation(s)
- Yuanbo Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Chenbin Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xinya Tong
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Sian Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xianjing Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Bujian Pan
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xiangwei Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Zhiyuan Chen
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xinyu Shi
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Yingying Hu
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiangyang Xue
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China.
| | - Mingdong Lu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
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m5C-Related Signatures for Predicting Prognosis in Cutaneous Melanoma with Machine Learning. JOURNAL OF ONCOLOGY 2021; 2021:6173206. [PMID: 34394351 PMCID: PMC8360728 DOI: 10.1155/2021/6173206] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/28/2021] [Indexed: 12/21/2022]
Abstract
Background Cutaneous melanoma (CM) is one of the most life-threatening primary skin cancers and is prone to distant metastases. A widespread presence of posttranscriptional modification of RNA, 5-methylcytosine (m5C), has been observed in human cancers. However, the potential mechanism of the tumorigenesis and prognosis in CM by dysregulated m5C-related regulators is obscure. Methods We use comprehensive bioinformatics analyses to explore the expression of m5C regulators in CM, the prognostic implications of the m5C regulators, the frequency of the copy number variant (CNV), and somatic mutations in m5C regulators. Additionally, the CM patients were divided into three clusters for better predicting clinical features and outcomes via consensus clustering of m5C regulators. Then, the risk score was established via Lasso Cox regression analysis. Next, the prognosis value and clinical characteristics of m5C-related signatures were further explored. Then, machine learning was used to recognize the outstanding m5C regulators to risk score. Finally, the expression level and clinical value of USUN6 were analyzed via the tissue microarray (TMA) cohort. Results We found that m5C regulators were dysregulated in CM, with a high frequency of somatic mutations and CNV alterations of the m5C regulatory gene in CM. Furthermore, 16 m5C-related proteins interacted with each other frequently, and we divided CM patients into three clusters to better predicting clinical features and outcomes. Then, five m5C regulators were selected as a risk score based on the LASSO model. The XGBoost algorithm recognized that NOP2 and NSUN6 were the most significant risk score contributors. Immunohistochemistry has verified that low expression of USUN6 was closely correlated with CM progression. Conclusion The m5C-related signatures can be used as new prognostic biomarkers and therapeutic targets for CM, and NSUN6 might play a vital role in tumorigenesis and malignant progression.
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Gao Y, Fang J. RNA 5-methylcytosine modification and its emerging role as an epitranscriptomic mark. RNA Biol 2021; 18:117-127. [PMID: 34288807 DOI: 10.1080/15476286.2021.1950993] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
5-methylcytosine (m5C) is identified as an abundant and conserved modification in various RNAs, including tRNAs, mRNAs, rRNAs, and other non-coding RNAs. The application of high-throughput sequencing and mass spectrometry allowed for the detection of m5C at a single-nucleotide resolution and at a global abundance separately; this contributes to a better understanding of m5C modification and its biological functions. m5C modification plays critical roles in diverse aspects of RNA processing, including tRNA stability, rRNA assembly, and mRNA translation. Notably, altered m5C modifications and mutated RNA m5C methyltransferases are associated with diverse pathological processes, such as nervous system disorders and cancers. This review may provide new sights of molecular mechanism and functional importance of m5C modification.
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Affiliation(s)
- Yaqi Gao
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingyuan Fang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Wood S, Willbanks A, Cheng JX. The Role of RNA Modifications and RNA-modifying Proteins in Cancer Therapy and Drug Resistance. Curr Cancer Drug Targets 2021; 21:326-352. [PMID: 33504307 DOI: 10.2174/1568009621666210127092828] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 11/22/2022]
Abstract
The advent of new genome-wide sequencing technologies has uncovered abnormal RNA modifications and RNA editing in a variety of human cancers. The discovery of reversible RNA N6-methyladenosine (RNA: m6A) by fat mass and obesity-associated protein (FTO) demethylase has led to exponential publications on the pathophysiological functions of m6A and its corresponding RNA modifying proteins (RMPs) in the past decade. Some excellent reviews have summarized the recent progress in this field. Compared to the extent of research into RNA: m6A and DNA 5-methylcytosine (DNA: m5C), much less is known about other RNA modifications and their associated RMPs, such as the role of RNA: m5C and its RNA cytosine methyltransferases (RCMTs) in cancer therapy and drug resistance. In this review, we will summarize the recent progress surrounding the function, intramolecular distribution and subcellular localization of several major RNA modifications, including 5' cap N7-methylguanosine (m7G) and 2'-O-methylation (Nm), m6A, m5C, A-to-I editing, and the associated RMPs. We will then discuss dysregulation of those RNA modifications and RMPs in cancer and their role in cancer therapy and drug resistance.
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Affiliation(s)
- Shaun Wood
- Department of Pathology, Hematopathology Section, University of Chicago, Chicago, IL60637, United States
| | - Amber Willbanks
- Department of Pathology, Hematopathology Section, University of Chicago, Chicago, IL60637, United States
| | - Jason X Cheng
- Department of Pathology, Hematopathology Section, University of Chicago, Chicago, IL60637, United States
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RNA methyltransferase NSUN2 promotes hypopharyngeal squamous cell carcinoma proliferation and migration by enhancing TEAD1 expression in an m 5C-dependent manner. Exp Cell Res 2021; 404:112664. [PMID: 34048786 DOI: 10.1016/j.yexcr.2021.112664] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 04/19/2021] [Accepted: 05/19/2021] [Indexed: 12/19/2022]
Abstract
RNA methyltransferase NSUN2 is involved in cell proliferation and invasion in a variety of tumors. However, the expression, function, and mechanism of NSUN2 in hypopharyngeal squamous cell carcinoma (HPSCC) remains unknown. We used a bioinformatics database, polymerase chain reaction, cell culture and transfection, immunohistochemistry, cell proliferation assay, wound healing experiments, transwell assays, western blotting, RNA-seq detection, dual-luciferase reporter assay, in vivo experiments, and a dot blot assay to evaluate the role of NSUN2 in HPSCC. NSUN2 mRNA and protein were highly expressed in HPSCC; NSUN2 knockdown in vitro and in vivo decreased cell proliferation and invasion. Studies have shown that TEAD1, a transcription factor, may act downstream of NSUN2 in HPSCC. NSUN2 was found to promote the proliferation and invasion of HPSCC by upregulating TEAD1 in an 5-methylcytosine-dependent manner, thereby representing an oncogene and potential new target for treating HPSCC.
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