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Liu S, Liao S, He J, Zhou Y, He Q. IGF2BP2: an m 6A reader that affects cellular function and disease progression. Cell Mol Biol Lett 2025; 30:43. [PMID: 40205577 PMCID: PMC11983839 DOI: 10.1186/s11658-025-00723-9] [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: 11/30/2024] [Accepted: 03/27/2025] [Indexed: 04/11/2025] Open
Abstract
Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2) is a widely studied N6-methyladenosine (m6A) modification reader, primarily functioning to recognize and bind to m6A modification sites on the mRNA of downstream target genes, thereby enhancing their stability. Previous studies have suggested that the IGF2BP2-m6A modification plays an essential role in cellular functions and the progression of various diseases. In this review, we focus on summarizing the molecular mechanisms by which IGF2BP2 enhances the mRNA stability of downstream target genes through m6A modification, thereby regulating cell ferroptosis, epithelial-mesenchymal transition (EMT), stemness, angiogenesis, inflammatory responses, and lipid metabolism, ultimately affecting disease progression. Additionally, we update the related research progress on IGF2BP2. This article aims to elucidate the effects of IGF2BP2 on cell ferroptosis, EMT, stemness, angiogenesis, inflammatory responses, and lipid metabolism, providing a new perspective for a comprehensive understanding of the relationship between IGF2BP2 and cell functions such as ferroptosis and EMT, as well as the potential for targeted IGF2BP2 therapy for tumors and other diseases.
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Affiliation(s)
- Siyi Liu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University/Hunan Cancer Hospital, Changsha, 410013, Hunan, China
- Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, 410011, Hunan, China
| | - Shan Liao
- Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Junyu He
- Department of Clinical Laboratory, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, 410007, Hunan, People's Republic of China
| | - Yanhong Zhou
- Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, 410011, Hunan, China.
| | - Qian He
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University/Hunan Cancer Hospital, Changsha, 410013, Hunan, China.
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Schultz S, Gomard-Henshaw K, Muller M. RNA Modifications and Their Role in Regulating KSHV Replication and Pathogenic Mechanisms. J Med Virol 2025; 97:e70140. [PMID: 39740054 DOI: 10.1002/jmv.70140] [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: 10/31/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 01/02/2025]
Abstract
Kaposi's sarcoma-associated herpesvirus is an oncogenic gammaherpesvirus that plays a major role in several human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The complexity of KSHV biology is reflected in the sophisticated regulation of its biphasic life cycle, consisting of a quiescent latent phase and virion-producing lytic replication. KSHV expresses coding and noncoding RNAs, including microRNAs and long noncoding RNAs, which play crucial roles in modulating viral gene expression, immune evasion, and intercellular communication. Recent studies have highlighted the importance of RNA modifications, also known as the epitranscriptome, in regulating KSHV-encoded RNAs, adding a novel layer of posttranscriptional control previously unknown. These RNA modifications, such as N6-methyladenosine, A-to-I editing, and N4-acetylcytidine, are involved in fine-tuning KSHV gene expression during both latency and lytic replication. Understanding the role of RNA modifications in KSHV infection is essential for revealing new regulatory mechanisms and identifying therapeutic opportunities. Targeting these RNA modifications could serve as a strategy to disrupt key viral processes, offering promising insights into KSHV pathogenesis and therapeutic interventions.
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Affiliation(s)
- S Schultz
- Microbiology Department, University of Massachusetts, Amherst, Massachusetts, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, USA
| | - K Gomard-Henshaw
- Microbiology Department, University of Massachusetts, Amherst, Massachusetts, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, USA
| | - M Muller
- Microbiology Department, University of Massachusetts, Amherst, Massachusetts, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, USA
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Zhu CY, Yang QW, Mu XY, Zhai YY, Zhao WY, Yin ZJ. Detecting the Tumor Prognostic Factors From the YTH Domain Family Through Integrative Pan-Cancer Analysis. Cancer Inform 2024; 23:11769351241300030. [PMID: 39553336 PMCID: PMC11569503 DOI: 10.1177/11769351241300030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/28/2024] [Indexed: 11/19/2024] Open
Abstract
Objectives Emerging evidence suggests that N6-methyladenosine (m6A) methylation plays a critical role in cancers through various mechanisms. This work aims to reveal the essential role of m6A methylation "readers" in regulation of cancer prognosis at the pan-cancer level. Methods Herein, we focused on one special protein family of the "readers" of m6A methylation, YT521-B homology (YTH) domain family genes, which were observed to be frequently dysregulated in tumor tissues and closely associated with cancer prognosis. Then, a comprehensive analysis of modulation in cancer prognosis was conducted by integrating RNA sequencing (RNAseq) datasets of YTH family genes and clinical information at the pan-cancer level. Results YTH family genes were significantly differentially expressed in most of the cancers, particularly increased in Gastrointestinal cancers, and decreased in Endocrine and Urologic cancers. In addition, they were observed to be associated with overall survival (OS) and disease-specific survival (DSS) with various extent, especially in lower grade glioma (LGG), thyroid cancer (THCA), liver hepatocellular carcinoma (LIHC) and kidney clear cell carcinoma (KIRC), so were some "writers" (METLL3, METLL14, WTAP) and "erasers" (FTO, ALKBH5). Further survival analysis illustrated that YTH family genes specifically YTHScore constructed by combining 5 YTH family genes, as well as RWEScore calculated by combining genes from "readers"-"writers"-"erasers" could dramatically distinguish tumor prognosis in 4 representative cancers. As expected, YTHScore presented an equally comparable prognostic classification with RWEScore. Finally, analysis of immune signatures and clinical characteristics implied that, the activity of the innate immune, diagnostic age, clinical stage, Tumor-Node-Metastasis (TNM) stage and immune types, might play specific roles in modulating tumor prognosis. Conclusions The study demonstrated that YTH family genes had the potential to predict tumor prognosis, in which the YTHScore illustrated equal ability to predict tumor prognosis compared to RWEScore, thus providing insights into prognostic biomarkers and therapeutic targets at the pan-cancer level.
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Affiliation(s)
- Chong-ying Zhu
- Department of Gynecology and Obstetrics, Ruijin Hospital, Center for Single-Cell Omics, School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qi-wei Yang
- Depanrtment of Urology, The Third Affiliated Hospital of Naval Military Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xin-yue Mu
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Yan-yu Zhai
- Department of Neurology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Zuo-jing Yin
- Department of Gynecology and Obstetrics, Ruijin Hospital, Center for Single-Cell Omics, School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Zhang G, Cheng C, Wang X, Wang S. N6-Methyladenosine methylation modification in breast cancer: current insights. J Transl Med 2024; 22:971. [PMID: 39468547 PMCID: PMC11514918 DOI: 10.1186/s12967-024-05771-x] [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: 08/11/2024] [Accepted: 10/16/2024] [Indexed: 10/30/2024] Open
Abstract
Breast cancer is the most common cancer type among women. Despite advanced treatment strategies, some patients still face challenges in disease control, prompting the exploration of new therapeutic approaches. N6-Methyladenosine (m6A) methylation modification regulates RNA and plays a crucial role in various tumor biological processes, closely linked to breast cancer occurrence, development, prognosis, and treatment. M6A regulators impact breast cancer progression, development, and drug resistance by modulating RNA metabolism and tumor-related pathways. Researchers have begun to understand the regulatory mechanisms of m6A methylation in breast cancer. This paper discusses the roles of m6A regulators in breast cancer progression, prognosis, and treatment, offering new perspectives for breast cancer diagnosis and treatment.
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Affiliation(s)
- Guangwen Zhang
- First Clinical Medical College of Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China.
| | - Chen Cheng
- Department of General Surgery, Jincheng General Hospital, Shanxi Medical University, Financial Street, Jincheng, 048006, Shanxi, China
| | - Xinle Wang
- First Clinical Medical College of Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
| | - Shiming Wang
- Department of Breast Surgery, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, Shanxi, China.
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Shoemaker R, Huang MF, Wu YS, Huang CS, Lee DF. Decoding the molecular symphony: interactions between the m 6A and p53 signaling pathways in cancer. NAR Cancer 2024; 6:zcae037. [PMID: 39329012 PMCID: PMC11426327 DOI: 10.1093/narcan/zcae037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/05/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant gene transcription, activation of oncogenic signaling and cancer development. Although mutations can occur at any point in the genetic sequence, missense mutations comprise the majority of observed p53 mutations in cancers regardless of whether the mutation is germline or somatic. One biological process involved in both mutant and wild-type p53 signaling is the N 6-methyladenosine (m6A) epitranscriptomic network, a type of post-transcriptional modification involved in over half of all eukaryotic mRNAs. Recently, a significant number of findings have demonstrated unique interactions between p53 and the m6A epitranscriptomic network in a variety of cancer types, shedding light on a previously uncharacterized connection that causes significant dysregulation. Cross-talk between wild-type or mutant p53 and the m6A readers, writers and erasers has been shown to impact cellular function and induce cancer formation by influencing various cancer hallmarks. Here, this review aims to summarize the complex interplay between the m6A epitranscriptome and p53 signaling pathway, highlighting its effects on tumorigenesis and other hallmarks of cancer, as well as identifying its therapeutic implications for the future.
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Affiliation(s)
- Rachel Shoemaker
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Mo-Fan Huang
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Ying-Si Wu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Cheng-Shuo Huang
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Dung-Fang Lee
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Huang Z, Lin G, Hong Y, Weng L, Zhu K, Zhuang W. High expression of AlkB homolog 5 suppresses the progression of non-small cell lung cancer by facilitating ferroptosis through m6A demethylation of SLC7A11. ENVIRONMENTAL TOXICOLOGY 2024; 39:4035-4046. [PMID: 38642004 DOI: 10.1002/tox.24272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/17/2024] [Accepted: 03/23/2024] [Indexed: 04/22/2024]
Abstract
OBJECTIVE Non-small cell lung cancer (NSCLC) is a prevailing LC characterized by poor outcomes. AlkB homolog 5 (ALKBH5) functions as a tumor suppressor in several cancers. This study delved into the role of ALKBH5 in NSCLC development. METHODS TCGA database predicted ALKBH5 expression in NSCLC patients. ALKBH5 levels in NSCLC and human bronchial epithelial cells were determined. pcDNA3.1-ALKBH5/NC, pcDNA3.1-SLC7A11/NC, and ferrostatin-1 were used to explore the interactions among ALKBH5, SLC7A11, and ferroptosis. SLC7A11 mRNA and its protein levels were measured by RT-qPCR and Western blot. Cell viability, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and Transwell. Total N6-methyladenosine (m6A) quantification and its enrichment on SLC7A11 mRNA were determined, followed by the observation of Ki67, ALKBH5 and SLC7A11-positive cell numbers. Glutathione (GSH), lipid reactive oxygen species (lipid-ROS), malondialdehyde (MDA), and iron ion contents were determined. Animal experiments further analyzed the role of ALKBH5 in tumor development and glutathione peroxidase 4 (GPX4) expression. RESULTS Bioinformatics analysis revealed the lowly-expressed ALKBH5 in LC patients. ALKBH5 was downregulated in NSCLC cells and its upregulation repressed proliferation activity, invasion, and migration, and facilitated apoptosis. ALKBH5 upregulation decreased GSH, increased lipid-ROS, MDA, and iron ion contents, and downregulated SLC7A11 by reducing m6A modification. SLC7A11 upregulation partly annulled the effect of ALKBH5 overexpression on cell ferroptosis and malignant behaviors. In vivo assays elucidated the suppression of ALKBH5 upregulation on tumor development and GPX4 levels. CONCLUSION ALKBH5 upregulation downregulates SLC7A11 transcription by decreasing m6A modification, thus promoting NSCLC cell ferroptosis and ultimately repressing NSCLC progression.
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Affiliation(s)
- Zhangzhou Huang
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Gen Lin
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yaping Hong
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Lihong Weng
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Kai Zhu
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Wu Zhuang
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
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Pan J, Tong F, Ren N, Ren L, Yang Y, Gao F, Xu Q. Role of N 6‑methyladenosine in the pathogenesis, diagnosis and treatment of prostate cancer (Review). Oncol Rep 2024; 51:88. [PMID: 38757383 PMCID: PMC11110010 DOI: 10.3892/or.2024.8747] [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: 11/02/2023] [Accepted: 04/19/2024] [Indexed: 05/18/2024] Open
Abstract
Prostate cancer (PCa) affects males of all racial and ethnic groups, and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to the late detection of the disease. PCa affects middle‑aged males between the ages of 45 and 60 years, and is the highest cause of cancer‑associated mortality in Western countries. As the most abundant and common mRNA modification in higher eukaryotes, N6‑methyladenosine (m6A) is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recent studies have found that abnormal expression levels of various m6A regulators significantly affect the development and progression of various types of cancer, including PCa. The present review discusses the influence of m6A regulatory factors on the pathogenesis and progression of PCa through mRNA modification based on the current state of research on m6A methylation modification in PCa. It is considered that the treatment of PCa with micro‑molecular drugs that target the epigenetics of the m6A regulator to correct abnormal m6A modifications is a direction for future research into current diagnostic and therapeutic approaches for PCa.
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Affiliation(s)
- Junjie Pan
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Fei Tong
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Ning Ren
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Lanqi Ren
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Yibei Yang
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Feng Gao
- Department of Urology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Qiaoping Xu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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Liu X, Xie X, Sui C, Liu X, Song M, Luo Q, Zhan P, Feng J, Liu J. Unraveling the cross-talk between N6-methyladenosine modification and non-coding RNAs in breast cancer: Mechanisms and clinical implications. Int J Cancer 2024; 154:1877-1889. [PMID: 38429857 DOI: 10.1002/ijc.34900] [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: 10/11/2023] [Revised: 02/02/2024] [Accepted: 02/14/2024] [Indexed: 03/03/2024]
Abstract
In recent years, breast cancer (BC) has surpassed lung cancer as the most common malignant tumor worldwide and remains the leading cause of cancer death in women. The etiology of BC usually involves dysregulation of epigenetic mechanisms and aberrant expression of certain non-coding RNAs (ncRNAs). N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, widely exists in ncRNAs to affect its biosynthesis and function, and is an important regulator of tumor-related signaling pathways. Interestingly, ncRNAs can also regulate or target m6A modification, playing a key role in cancer progression. However, the m6A-ncRNAs regulatory network in BC has not been fully elucidated, especially the regulation of m6A modification by ncRNAs. Therefore, in this review, we comprehensively summarize the interaction mechanisms and biological significance of m6A modifications and ncRNAs in BC. Meanwhile, we also focused on the clinical application value of m6A modification in BC diagnosis and prognosis, intending to explore new biomarkers and potential therapeutic targets.
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Affiliation(s)
- Xuan Liu
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Xuelong Xie
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Chentao Sui
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Xuexue Liu
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Miao Song
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Qing Luo
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Ping Zhan
- Department of Obstetrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jia Feng
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
| | - Jinbo Liu
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China
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Wu X, Chen H, Li K, Zhang H, Li K, Tan H. The biological function of the N6-Methyladenosine reader YTHDC2 and its role in diseases. J Transl Med 2024; 22:490. [PMID: 38790013 PMCID: PMC11119022 DOI: 10.1186/s12967-024-05293-6] [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: 03/25/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
N6-methyladenosine (m6A) stands as the most prevalent modified form of RNA in eukaryotes, pivotal in various biological processes such as regulating RNA stability, translation, and transcription. All members within the YT521-B homology (YTH) gene family are categorized as m6A reading proteins, capable of identifying and binding m6A modifications on RNA, thereby regulating RNA metabolism and functioning across diverse physiological processes. YTH domain-containing 2 (YTHDC2), identified as the latest member of the YTH family, has only recently started to emerge for its biological function. Numerous studies have underscored the significance of YTHDC2 in human physiology, highlighting its involvement in both tumor progression and non-tumor diseases. Consequently, this review aims to further elucidate the pathological mechanisms of YTHDC2 by summarizing its functions and roles in tumors and other diseases, with a particular focus on its downstream molecular targets and signaling pathways.
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Affiliation(s)
- Xudong Wu
- Department of Thoracic Surgery, The Third Hospital of Changsha, Changsha, 410015, Hunan, People's Republic of China
| | - Hui Chen
- Department of Thoracic Surgery, The Third Hospital of Changsha, Changsha, 410015, Hunan, People's Republic of China
| | - Kai Li
- Department of Thoracic Surgery, The Third Hospital of Changsha, Changsha, 410015, Hunan, People's Republic of China
| | - Hong Zhang
- Department of Thoracic Surgery, The Third Hospital of Changsha, Changsha, 410015, Hunan, People's Republic of China
| | - Kai Li
- Department of Thoracic Surgery, Xiangxi Autonomous Prefecture People's Hospital, Jishou, 410015, Hunan, People's Republic of China
| | - Haoyu Tan
- Department of Cardio-vascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China.
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Man J, Zhang Q, Zhao T, Sun D, Sun W, Long K, Zhang Z. Oxidative Stress Induced by Arsenite is Involved in YTHDF2 Phase Separation. Biol Trace Elem Res 2024; 202:885-899. [PMID: 37310554 DOI: 10.1007/s12011-023-03728-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/05/2023] [Indexed: 06/14/2023]
Abstract
YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) undergoes phase separation in response to the stimulation of high concentration of arsenite, suggesting that oxidative stress, the major mechanism of arsenite toxicity, may play a role in YTHDF2 phase separation. However, whether arsenite-induced oxidative stress is involved in phase separation of YTHDF2 has yet to be established. To explore the effect of arsenite-induced oxidative stress on YTHDF2 phase separation, the levels of oxidative stress, YTHDF2 phase separation, and N6-methyladenosine (m6A) in human keratinocytes were detected after exposure to various concentrations of sodium arsenite (0-500 µM; 1 h) and antioxidant N-acetylcysteine (0-10 mM; 2 h). We found that arsenite promoted oxidative stress and YTHDF2 phase separation in a concentration-dependent manner. In contrast, pretreatment with N-acetylcysteine significantly relieved arsenate-induced oxidative stress and inhibited YTHDF2 phase separation. As one of the key factors to YTHDF2 phase separation, N6-methyladenosine (m6A) levels in human keratinocytes were significantly increased after arsenite exposure, accompanied by upregulation of m6A methylesterase levels and downregulation of m6A demethylases levels. On the contrary, N-acetylcysteine mitigated the arsenite-induced increase of m6A and m6A methylesterase and the arsenite-induced decrease in m6A demethylase. Collectively, our study firstly revealed that oxidative stress induced by arsenite plays an important role in YTHDF2 phase separation driven by m6A modification, which provides new insights into the arsenite toxicity from the phase-separation perspective.
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Affiliation(s)
- Jin Man
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qian Zhang
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Tianhe Zhao
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Donglei Sun
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Weilian Sun
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Keyan Long
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Zunzhen Zhang
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, 610041, Sichuan, China.
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Luo W, Zhou Y, Wang J, Wang K, Lin Q, Li Y, Xie Y, Li M, Wang J, Xiong L. YTHDF1's Regulatory Involvement in Breast Cancer Prognosis, Immunity, and the ceRNA Network. Int J Mol Sci 2024; 25:1879. [PMID: 38339157 PMCID: PMC10856278 DOI: 10.3390/ijms25031879] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/17/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), an m6A reader, has a role in the development and progression of breast cancer as well as the immunological microenvironment. The networks of competing endogenous RNA in cancer have received much attention in research. In tumor gene therapy, the regulatory networks of m6A and competing endogenous RNA are increasingly emerging as a new route. We evaluated the relationship between the YTHDF1 expression, overall survival, and clinicopathology of breast cancer using TCGA, PrognoScan, and other datasets. We used Western blot to demonstrate that YTHDF1 is substantially expressed in breast cancer tissues. Furthermore, we explored YTHDF1's functions in the tumor mutational burden, microsatellite instability, and tumor microenvironment. Our findings indicate that YTHDF1 is a critical component of the m6A regulatory proteins in breast cancer and may have a particular function in the immunological microenvironment. Crucially, we investigated the relationship between YTHDF1 and the associated competitive endogenous RNA regulatory networks, innovatively creating three such networks (Dehydrogenase/Reductase 4-Antisense RNA 1-miR-378g-YTHDF1, HLA Complex Group 9-miR-378g-YTHDF1, Taurine Up-regulated 1-miR-378g-YTHDF1). Furthermore, we showed that miR-378g could inhibit the expression of YTHDF1, and that miR-378g/YTHDF1 could impact MDA-MB-231 proliferation. We speculate that YTHDF1 may serve as a biomarker for poor prognosis and differential diagnosis, impact the growth of breast cancer cells via the ceRNA network axis, and be a target for immunotherapy against breast cancer.
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Affiliation(s)
- Wenting Luo
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Youjia Zhou
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China
| | - Jiayang Wang
- First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Keqin Wang
- First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Qing Lin
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China
| | - Yuqiu Li
- Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Yujie Xie
- College of Pharmacy, Nanchang University, Nanchang 330006, China
| | - Miao Li
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Jie Wang
- Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University, Xiamen 361023, China
| | - Lixia Xiong
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China
- Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University, Xiamen 361023, China
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12
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Xu Q, Ren N, Ren L, Yang Y, Pan J, Shang H. RNA m6A methylation regulators in liver cancer. Cancer Cell Int 2024; 24:1. [PMID: 38166832 PMCID: PMC10763310 DOI: 10.1186/s12935-023-03197-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 12/26/2023] [Indexed: 01/05/2024] Open
Abstract
Liver cancer is one of the most common cancers in the world and a primary cause of cancer-related death. In recent years, despite the great development of diagnostic methods and targeted therapies for liver cancer, the incidence and mortality of liver cancer are still on the rise. As a universal post-transcriptional modification, N6-methyladenosine (m6A) modification accomplishes a dynamic and reversible m6A modification process, which is executed by three types of regulators, methyltransferases (called writers), demethylases (called erasers) and m6A-binding proteins (called readers). Many studies have shown that m6A RNA methylation has an important impact on RNA metabolism, whereas its regulation exception is bound up with the occurrence of human malignant tumors. Aberrant methylation of m6A RNA and the expression of related regulatory factors may be of the essence in the pathogenesis and progression of liver cancer, yet the precise molecular mechanism remains unclear. In this paper, we review the current research situations of m6A methylation in liver cancer. Among the rest, we detail the mechanism by which methyltransferases, demethylases and m6A binding proteins regulate the occurrence and development of liver cancer by modifying mRNA. As well as the potential effect of m6A regulators in hepatocarcinogenesis and progression. New ideas and approaches will be given to the prevention and treatment of liver cancer through the following relevant research results.
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Affiliation(s)
- Qiaoping Xu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China
| | - Ning Ren
- Fourth Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Lanqi Ren
- Fourth Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Yibei Yang
- Fourth Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Junjie Pan
- Fourth Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Hongkai Shang
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China.
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
- Department of the Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
- Department of Gynecology, Hangzhou First People's Hospital, Hangzhou, China.
- Department of Gynecology, Westlake University School of Medicine, Hangzhou, China.
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13
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Xia T, Dai X, Sang M, Zhang X, Xu F, Wu J, Shi L, Wei J, Ding Q. IGF2BP2 Drives Cell Cycle Progression in Triple-Negative Breast Cancer by Recruiting EIF4A1 to Promote the m6A-Modified CDK6 Translation Initiation Process. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305142. [PMID: 37983610 PMCID: PMC10767445 DOI: 10.1002/advs.202305142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/02/2023] [Indexed: 11/22/2023]
Abstract
IGF2BP2 is a new identified N6-methyladenosine (m6A) reader and associated with poor prognosis in many tumors. However, its role and related mechanism in breast cancer, especially in triple-negative breast cancer (TNBC), remains unclear. In this study, it is found that IGF2BP2 is highly expressed in TNBC due to the lower methylation level in its promoter region. Functional and mechanical studies displayed that IGF2BP2 could promote TNBC proliferation and the G1/S phase transition of the cell cycle via directly regulating CDK6 in an m6A-dependent manner. Surprising, the regulation of protein levels of CDK6 by IGF2BP2 is related to the changes in translation rate during translation initiation, rather than mRNA stability. Moreover, EIF4A1 is found to be recruited by IGF2BP2 to promote the translation output of CDK6, providing new evidence for a regulatory role of IGF2BP2 between m6A methylation and translation. Downregulation of IGF2BP2 in TNBC cell could enhance the sensitivity to abemaciclib, a CDK4/6 inhibitor. To sum up, our study revealed IGF2BP2 could facilitate the translation output of CDK6 via recruiting EIF4A1 and also provided a potential therapeutic target for the diagnosis and treatment of TNBC, as well as a new strategy for broadening the drug indications for CDK4/6 inhibitors.
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Affiliation(s)
- Tian Xia
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Xin‐Yuan Dai
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Ming‐Yi Sang
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Xu Zhang
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Feng Xu
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Jing Wu
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Liang Shi
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
| | - Ji‐Fu Wei
- Department of PharmacyJiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing210029China
| | - Qiang Ding
- Jiangsu Breast Disease CenterThe First Affiliated Hospital with Nanjing Medical University300 Guangzhou RoadNanjing210029China
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14
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Li C, Li B, Wang H, Qu L, Liu H, Weng C, Han J, Li Y. Role of N6-methyladenosine methylation in glioma: recent insights and future directions. Cell Mol Biol Lett 2023; 28:103. [PMID: 38072944 PMCID: PMC10712162 DOI: 10.1186/s11658-023-00514-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous cancer cell population. There is a significantly high mortality rate in GBM patients. Molecular biomarkers related to GBM malignancy may have prognostic values in predicting survival outcomes and therapeutic responses, especially in patients with high-grade gliomas. In particular, N6-methyladenine (m6A) mRNA modification is the most abundant form of post-transcriptional RNA modification in mammals and is involved in regulating mRNA translation and degradation. Cumulative findings indicate that m6A methylation plays a crucial part in neurogenesis and glioma pathogenesis. In this review, we summarize recent advances regarding the functional significance of m6A modification and its regulatory factors in glioma occurrence and progression. Significant advancement of m6A methylation-associated regulators as potential therapeutic targets is also discussed.
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Affiliation(s)
- Chunlin Li
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Bowen Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250000, Shandong, China
| | - Hui Wang
- Department of Acupuncture, Zaozhuang Traditional Chinese Medicine Hospital, Zaozhuang, 277000, Shandong, China
| | - Linglong Qu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250000, Shandong, China
| | - Hui Liu
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250000, Shandong, China
| | - Chao Weng
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Jinming Han
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Yuan Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Suzhou Research Institute of Shandong University, Suzhou 215123, China.
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15
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Yang J, Wang Y, Huang Z, Jiang Y, Pan X, Dong X, Yang G. Roles of rRNA N-methyladenosine modification in the function of ribosomes. Cell Biochem Funct 2023; 41:1106-1114. [PMID: 38041420 DOI: 10.1002/cbf.3891] [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: 07/10/2023] [Revised: 10/19/2023] [Accepted: 11/17/2023] [Indexed: 12/03/2023]
Abstract
The N-methyladenosine (m6A) modification of ribosomal RNA (rRNA) plays critical roles in regulating the function of ribosomes, the essential molecular machines that translate genetic information from mRNA into proteins. Specifically, m6A modification affects ribosome biogenesis, stability, and function by regulating the processing and maturation of rRNA, the assembly and composition of ribosomes, and the accuracy and efficiency of translation. Furthermore, m6A modification allows for dynamic regulation of translation in response to environmental and cellular signals. Therefore, a deeper understanding of the mechanisms and functions of m6A modification in rRNA will advance our knowledge of ribosome-mediated gene expression and facilitate the development of new therapeutic strategies for ribosome-related diseases.
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Affiliation(s)
- Jingyi Yang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Yameng Wang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Zekai Huang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Yashuang Jiang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Xiaolei Pan
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Xiaowei Dong
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Geng Yang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China
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16
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Dorgham MG, Elliott BA, Holley CL, Mansfield KD. m6A regulates breast cancer proliferation and migration through stage-dependent changes in Epithelial to Mesenchymal Transition gene expression. Front Oncol 2023; 13:1268977. [PMID: 38023205 PMCID: PMC10661887 DOI: 10.3389/fonc.2023.1268977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
While many factors have been implicated in breast cancer progression, effective treatments are still lacking. In recent years, it has become clear that posttranscriptional regulation plays a key role in the aberrant gene expression underlying malignancy and metastasis. For example, the mRNA modification N6-methyladenosine (m6A) is involved in numerous post-transcriptional regulation processes and has been implicated in many cancer types, including breast cancer. Despite intense study, even within a single type of cancer, there is little consensus, and often conflicting results, as to the role of m6A, suggesting other factors must influence the process. The goal of this study was to determine if the effects of m6A manipulation on proliferation and migration differed based on the stage of disease progression. Using the MCF10 model of breast cancer, we reduced m6A levels by targeting METTL3, the main cellular m6A RNA methyltransferase. Knocking down Mettl3 at different stages of breast cancer progression indeed shows unique effects at each stage. The early-stage breast cancer line showed a more proliferative phenotype with the knockdown of Mettl3 while the transformed breast cancer line showed a more migratory phenotype. Interestingly, the metastasized breast cancer cell line showed almost no effect on phenotype with the knockdown of Mettl3. Furthermore, transcriptome wide analysis revealed EMT as the probable pathway influencing the phenotypic changes. The results of this study may begin to address the controversy of m6A's role in cancer and suggest that m6A may have a dynamic role in cancer that depends on the stage of progression.
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Affiliation(s)
- Mohammed G. Dorgham
- Biochemistry and Molecular Biology Department, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Brittany A. Elliott
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | | | - Kyle D. Mansfield
- Biochemistry and Molecular Biology Department, Brody School of Medicine, East Carolina University, Greenville, NC, United States
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17
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Wang Q, Fan X, Sheng Q, Yang M, Zhou P, Lu S, Gao Y, Kong Z, Shen N, Lv Z, Wang R. N6-methyladenosine methylation in kidney injury. Clin Epigenetics 2023; 15:170. [PMID: 37865763 PMCID: PMC10590532 DOI: 10.1186/s13148-023-01586-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/11/2023] [Indexed: 10/23/2023] Open
Abstract
Multiple mechanisms are involved in kidney damage, among which the role of epigenetic modifications in the occurrence and development of kidney diseases is constantly being revealed. However, N6-methyladenosine (M6A), a well-known post-transcriptional modification, has been regarded as the most prevalent epigenetic modifications in higher eukaryotic, which is involved in various biological processes of cells such as maintaining the stability of mRNA. The role of M6A modification in the mechanism of kidney damage has attracted widespread attention. In this review, we mainly summarize the role of M6A modification in the progression of kidney diseases from the following aspects: the regulatory pattern of N6-methyladenosine, the critical roles of N6-methyladenosine in chronic kidney disease, acute kidney injury and renal cell carcinoma, and then reveal its potential significance in the diagnosis and treatment of various kidney diseases. A better understanding of this field will be helpful for future research and clinical treatment of kidney diseases.
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Affiliation(s)
- Qimeng Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Xiaoting Fan
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Qinghao Sheng
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Meilin Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ping Zhou
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Shangwei Lu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ying Gao
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Zhijuan Kong
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ning Shen
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
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18
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Hu J, Lin H, Wang C, Su Q, Cao B. METTL14‑mediated RNA methylation in digestive system tumors. Int J Mol Med 2023; 52:86. [PMID: 37539726 PMCID: PMC10555478 DOI: 10.3892/ijmm.2023.5289] [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: 03/03/2023] [Accepted: 07/06/2023] [Indexed: 08/05/2023] Open
Abstract
N6‑methyladenosine (m6A) RNA methylation is one of the most common post‑transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of the mRNA life cycle, specifically regulating its stability, splicing, export and translation. Methyltransferase‑like 14 (METTL14) is a particularly important m6A methylation 'writer' that can recognize RNA substrates. METTL14 has been documented to improve the activity and catalytic efficiency of METTL3. However, as individual proteins they can also regulate different biological processes. Malignancies in the digestive system are some of the most common malignancies found in humans, which are typically associated with poor prognoses with limited clinical solutions. METTL14‑mediated methylation has been implicated in both the potentiation and inhibition of digestive system tumor growth, cell invasion and metastasis, in addition to drug resistance. In the present review, the research progress and regulatory mechanisms of METTL14‑mediated methylation in digestive system malignancies were summarized. In addition, future research directions and the potential for its clinical application were examined.
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Affiliation(s)
- Jiexuan Hu
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Haishan Lin
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Cong Wang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Qiang Su
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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19
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Zhang N, Sun Y, Mei Z, He Z, Gu S. Novel insights into mutual regulation between N 6-methyladenosine modification and LncRNAs in tumors. Cancer Cell Int 2023; 23:127. [PMID: 37365581 DOI: 10.1186/s12935-023-02955-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023] Open
Abstract
N6-methyladenosine (m6A), one of the most common RNA methylation modifications, has emerged in recent years as a new layer of the regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification, m6A not only occurs on mRNAs but also on Long non-coding RNAs (LncRNAs). As we all known, despite LncRNAs cannot encode proteins, they affect the expression of proteins by interacting with mRNAs or miRNAs, thus playing important roles in the occurrence and development of a variety of tumors. Up to now, it has been widely accepted that m6A modification on LncRNAs affects the fate of the corresponding LncRNAs. Interestingly, levels and functions of m6A modifications are also mediated by LncRNAs through affecting the m6A methyltransferases (METTL3, METTL14, WTAP, METTL16, etc.), demethylases (FTO, ALKBH5) and methyl-binding proteins (YTHDFs, YTHDCs, IGF2BPs, HNRNPs, etc.), which are collectively referred to as "m6A regulators". In this review, we summarized the mutual regulation mechanisms between N6-methyladenosine modification and LncRNAs in cancer progression, metastasis, invasion and drug resistance. In detail, we focus on the specific mechanisms of m6A modification, which is mediated by methyltransferases and demethylases, involves in the regulation of LncRNA levels and functions in the first part. And section two intensively displays the mediation roles of LncRNAs in m6A modification via changing the regulatory proteins. At last part, we described the interaction effects between LncRNAs and methyl-binding proteins of m6A modification during various tumor occurrence and development.
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Affiliation(s)
- Nan Zhang
- School of Public Health, Institute of Preventive Medicine, Dali University, No. 22, Wanhua Road, Dali, 671000, Yunnan, People's Republic of China
| | - Yifei Sun
- School of Public Health, Institute of Preventive Medicine, Dali University, No. 22, Wanhua Road, Dali, 671000, Yunnan, People's Republic of China
| | - Zongqin Mei
- School of Public Health, Institute of Preventive Medicine, Dali University, No. 22, Wanhua Road, Dali, 671000, Yunnan, People's Republic of China
| | - Zuoshun He
- School of Public Health, Institute of Preventive Medicine, Dali University, No. 22, Wanhua Road, Dali, 671000, Yunnan, People's Republic of China.
| | - Shiyan Gu
- School of Public Health, Institute of Preventive Medicine, Dali University, No. 22, Wanhua Road, Dali, 671000, Yunnan, People's Republic of China.
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20
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Gómez de Cedrón M, Moreno Palomares R, Ramírez de Molina A. Metabolo-epigenetic interplay provides targeted nutritional interventions in chronic diseases and ageing. Front Oncol 2023; 13:1169168. [PMID: 37404756 PMCID: PMC10315663 DOI: 10.3389/fonc.2023.1169168] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/24/2023] [Indexed: 07/06/2023] Open
Abstract
Epigenetic modifications are chemical modifications that affect gene expression without altering DNA sequences. In particular, epigenetic chemical modifications can occur on histone proteins -mainly acetylation, methylation-, and on DNA and RNA molecules -mainly methylation-. Additional mechanisms, such as RNA-mediated regulation of gene expression and determinants of the genomic architecture can also affect gene expression. Importantly, depending on the cellular context and environment, epigenetic processes can drive developmental programs as well as functional plasticity. However, misbalanced epigenetic regulation can result in disease, particularly in the context of metabolic diseases, cancer, and ageing. Non-communicable chronic diseases (NCCD) and ageing share common features including altered metabolism, systemic meta-inflammation, dysfunctional immune system responses, and oxidative stress, among others. In this scenario, unbalanced diets, such as high sugar and high saturated fatty acids consumption, together with sedentary habits, are risk factors implicated in the development of NCCD and premature ageing. The nutritional and metabolic status of individuals interact with epigenetics at different levels. Thus, it is crucial to understand how we can modulate epigenetic marks through both lifestyle habits and targeted clinical interventions -including fasting mimicking diets, nutraceuticals, and bioactive compounds- which will contribute to restore the metabolic homeostasis in NCCD. Here, we first describe key metabolites from cellular metabolic pathways used as substrates to "write" the epigenetic marks; and cofactors that modulate the activity of the epigenetic enzymes; then, we briefly show how metabolic and epigenetic imbalances may result in disease; and, finally, we show several examples of nutritional interventions - diet based interventions, bioactive compounds, and nutraceuticals- and exercise to counteract epigenetic alterations.
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Affiliation(s)
- Marta Gómez de Cedrón
- Molecular Oncology Group, IMDEA Food Institute, CEI UAM, CSIC, Madrid, Spain
- Cell Metabolism Unit, IMDEA Food Institute, CEI UAM, CSIC, Madrid, Spain
| | - Rocío Moreno Palomares
- Molecular Oncology Group, IMDEA Food Institute, CEI UAM, CSIC, Madrid, Spain
- FORCHRONIC S.L, Avda. Industria, Madrid, Spain
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The Effect of N6-Methyladenosine Regulators and m6A Reader YTHDC1-Mediated N6-Methyladenosine Modification Is Involved in Oxidative Stress in Human Aortic Dissection. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:3918393. [PMID: 36819785 PMCID: PMC9935809 DOI: 10.1155/2023/3918393] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/04/2022] [Accepted: 11/24/2022] [Indexed: 02/11/2023]
Abstract
Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.
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Chen J, Ye M, Bai J, Hu C, Lu F, Gu D, Yu P, Tang Q. Novel insights into the interplay between m6A modification and programmed cell death in cancer. Int J Biol Sci 2023; 19:1748-1763. [PMID: 37063421 PMCID: PMC10092764 DOI: 10.7150/ijbs.81000] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/08/2023] [Indexed: 04/18/2023] Open
Abstract
N6-methyladenosine (m6A) methylation, the most prevalent and abundant RNA modification in eukaryotes, has recently become a hot research topic. Several studies have indicated that m6A modification is dysregulated during the progression of multiple diseases, especially in cancer development. Programmed cell death (PCD) is an active and orderly method of cell death in the development of organisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. As the study of PCD has become increasingly profound, accumulating evidence has revealed the mutual regulation of m6A modification and PCD, and their interaction can further influence the sensitivity of cancer treatment. In this review, we summarize the recent advances in m6A modification and PCD in terms of their interplay and potential mechanisms, as well as cancer therapeutic resistance. Our study provides promising insights and future directions for the examination and treatment of cancers.
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Affiliation(s)
| | | | | | | | | | | | | | - Qiyun Tang
- ✉ Corresponding author: Qiyun Tang, Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, NO. 300 Guangzhou Road, Nanjing, China.
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23
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Micaelli M, Dalle Vedove A, Cerofolini L, Vigna J, Sighel D, Zaccara S, Bonomo I, Poulentzas G, Rosatti EF, Cazzanelli G, Alunno L, Belli R, Peroni D, Dassi E, Murakami S, Jaffrey SR, Fragai M, Mancini I, Lolli G, Quattrone A, Provenzani A. Small-Molecule Ebselen Binds to YTHDF Proteins Interfering with the Recognition of N 6-Methyladenosine-Modified RNAs. ACS Pharmacol Transl Sci 2022; 5:872-891. [PMID: 36268123 PMCID: PMC9578143 DOI: 10.1021/acsptsci.2c00008] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Indexed: 11/28/2022]
Abstract
YTHDF proteins bind the N 6-methyladenosine (m6A)-modified mRNAs, influencing their processing, stability, and translation. Therefore, the members of this protein family play crucial roles in gene regulation and several physiological and pathophysiological conditions. YTHDF proteins contain a hydrophobic pocket that accommodates the m6A embedded in the RRACH consensus sequence on mRNAs. We exploited the presence of this cage to set up an m6A-competitive assay and performed a high-throughput screen aimed at identifying ligands binding in the m6A pocket. We report the organoselenium compound ebselen as the first-in-class inhibitor of the YTHDF m6A-binding domain. Ebselen, whose interaction with YTHDF proteins was validated via orthogonal assays, cannot discriminate between the binding domains of the three YTHDF paralogs but can disrupt the interaction of the YTHDF m6A domain with the m6A-decorated mRNA targets. X-ray, mass spectrometry, and NMR studies indicate that in YTHDF1 ebselen binds close to the m6A cage, covalently to the Cys412 cysteine, or interacts reversibly depending on the reducing environment. We also showed that ebselen engages YTHDF proteins within cells, interfering with their mRNA binding. Finally, we produced a series of ebselen structural analogs that can interact with the YTHDF m6A domain, proving that ebselen expansion is amenable for developing new inhibitors. Our work demonstrates the feasibility of drugging the YTH domain in YTHDF proteins and opens new avenues for the development of disruptors of m6A recognition.
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Affiliation(s)
- Mariachiara Micaelli
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Andrea Dalle Vedove
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Linda Cerofolini
- Magnetic
Resonance Center (CERM)—Department of Chemistry “Ugo
Schiff”, University of Florence, 50019Florence, Italy
- Consorzio
Interuniversitario Risonanze Magnetiche di Metalloproteine (CIRMMP), 50019Florence, Italy
| | - Jacopo Vigna
- Department
of Physics, University of Trento, 38123Trento, Italy
| | - Denise Sighel
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Sara Zaccara
- Department
of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York10065, United States
| | - Isabelle Bonomo
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Georgios Poulentzas
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Emanuele Filiberto Rosatti
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Giulia Cazzanelli
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Laura Alunno
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Romina Belli
- Department
of Cellular, Computational and Integrative Biology, CIBIO, Mass Spectrometry
Facility, University of Trento, 38123Trento, Italy
| | - Daniele Peroni
- Department
of Cellular, Computational and Integrative Biology, CIBIO, Mass Spectrometry
Facility, University of Trento, 38123Trento, Italy
| | - Erik Dassi
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Shino Murakami
- Department
of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York10065, United States
| | - Samie R. Jaffrey
- Department
of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York10065, United States
| | - Marco Fragai
- Magnetic
Resonance Center (CERM)—Department of Chemistry “Ugo
Schiff”, University of Florence, 50019Florence, Italy
- Consorzio
Interuniversitario Risonanze Magnetiche di Metalloproteine (CIRMMP), 50019Florence, Italy
| | - Ines Mancini
- Department
of Physics, University of Trento, 38123Trento, Italy
| | - Graziano Lolli
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Alessandro Quattrone
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
| | - Alessandro Provenzani
- Department
of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, 38123Trento, Italy
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Zhou M, Dong M, Yang X, Gong J, Liao X, Zhang Q, Liu Z. The emerging roles and mechanism of m6a in breast cancer progression. Front Genet 2022; 13:983564. [PMID: 36035182 PMCID: PMC9399344 DOI: 10.3389/fgene.2022.983564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 07/18/2022] [Indexed: 12/30/2022] Open
Abstract
Breast cancer (BC) has continued to be the leading cause of cancer deaths in women, accompanied by highly molecular heterogeneity. N6-methyladenosine (m6A), a methylation that happens on adenosine N6, is the most abundant internal mRNA modification type in eukaryotic cells. Functionally, m6A methylation is a reversible modification process and is regulated by 3 enzymes with different functions, namely “writer”, “reader”, and “eraser”. Abnormal m6A modifications trigger the expression, activation, or inhibition of key signaling molecules in critical signaling pathways and the regulatory factors acting on them in BC. These m6A-related enzymes can not only be used as markers for accurate diagnosis, prediction of prognosis, and risk model construction, but also as effective targets for BC treatment. Here, we have emphasized the roles of different types of m6A-related enzymes reported in BC proliferation, invasion, and metastasis, as well as immune regulation. The comprehensive and in-depth exploration of the molecular mechanisms related to m6A will benefit in finding effective potential targets and effective stratified management of BC.
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Affiliation(s)
- Mengying Zhou
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, China
| | - Menglu Dong
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue Yang
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Gong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinghua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, China
- *Correspondence: Xinghua Liao, ; Qi Zhang, ; Zeming Liu,
| | - Qi Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Xinghua Liao, ; Qi Zhang, ; Zeming Liu,
| | - Zeming Liu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Xinghua Liao, ; Qi Zhang, ; Zeming Liu,
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Zhang F, Ran Y, Tahir M, Li Z, Wang J, Chen X. Regulation of N6-methyladenosine (m6A) RNA methylation in microglia-mediated inflammation and ischemic stroke. Front Cell Neurosci 2022; 16:955222. [PMID: 35990887 PMCID: PMC9386152 DOI: 10.3389/fncel.2022.955222] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/12/2022] [Indexed: 11/17/2022] Open
Abstract
N6-methyladenosine (m6A) is the most abundant post-transcription modification, widely occurring in eukaryotic mRNA and non-coding RNA. m6A modification is highly enriched in the mammalian brain and is associated with neurological diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Ischemic stroke (IS) was discovered to alter the cerebral m6A epi-transcriptome, which might have functional implications in post-stroke pathophysiology. Moreover, it is observed that m6A modification could regulate microglia’s pro-inflammatory and anti-inflammatory responses. Given the critical regulatory role of microglia in the inflammatory processes in the central nervous system (CNS), we speculate that m6A modification could modulate the post-stroke microglial inflammatory responses. This review summarizes the vital regulatory roles of m6A modification in microglia-mediated inflammation and IS. Stroke is associated with a high recurrence rate, understanding the relationship between m6A modification and stroke may help stroke rehabilitation and develop novel therapies in the future.
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Affiliation(s)
- Fangfang Zhang
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Yuanyuan Ran
- Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | - Muhammad Tahir
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Zihan Li
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Jianan Wang
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Xuechai Chen
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- *Correspondence: Xuechai Chen,
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26
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Han J, Kong H, Wang X, Zhang XA. Novel insights into the interaction between N6-methyladenosine methylation and noncoding RNAs in musculoskeletal disorders. Cell Prolif 2022; 55:e13294. [PMID: 35735243 PMCID: PMC9528765 DOI: 10.1111/cpr.13294] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Musculoskeletal disorder (MSD) are a class of inflammatory and degener-ative diseases, but the precise molecular mechanisms are still poorly understood. Noncoding RNA (ncRNA) N6-methyladenosine (m6A) modification plays an essential role in the pathophysiological process of MSD. This review summarized the interaction be-tween m6A RNA methylation and ncRNAs in the molecular regulatory mechanism of MSD. It provides a new perspective for the pathophysiological mechanism and ncRNA m6A targeted therapy of MSD. METHODS A comprehensive search of databases was conducted with musculoskeletal disorders, noncoding RNA, N6-methyladenosine, intervertebral disc degeneration, oste-oporosis, osteosarcoma, osteoarthritis, skeletal muscle, bone, and cartilage as the key-words. Then, summarized all the relevant articles. RESULTS Intervertebral disc degeneration (IDD), osteoporosis (OP), osteosarcoma (OS), and osteoarthritis (OA) are common MSDs that affect muscle, bone, cartilage, and joint, leading to limited movement, pain, and disability. However, the precise pathogenesis remains unclear, and no effective treatment and drug is available at present. Numerous studies confirmed that the mutual regulation between m6A and ncRNAs (i.e., microRNAs, long ncRNAs, and circular RNAs) was found in MSD, m6A modification can regulate ncRNAs, and ncRNAs can also target m6A regulators. ncRNA m6A modification plays an essential role in the pathophysiological process of MSDs by regulating the homeostasis of skeletal muscle, bone, and cartilage. CONCLUSION m6A interacts with ncRNAs to regulate multiple biological processes and plays important roles in IDD, OP, OS, and OA. These studies provide new insights into the pathophysiological mechanism of MSD and targeting m6A-modified ncRNAs may be a promising therapy approach.
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Affiliation(s)
- Juanjuan Han
- College of Kinesiology, Shenyang Sport University, Shenyang, China.,Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Hui Kong
- College of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Xueqiang Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China.,Department of Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
| | - Xin-An Zhang
- College of Kinesiology, Shenyang Sport University, Shenyang, China
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27
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Liu Y, Zhu T, Jiang Y, Bu J, Zhu X, Gu X. The Key Role of RNA Modification in Breast Cancer. Front Cell Dev Biol 2022; 10:885133. [PMID: 35721510 PMCID: PMC9198488 DOI: 10.3389/fcell.2022.885133] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 04/25/2022] [Indexed: 12/09/2022] Open
Abstract
The modulation of the function and expression of epigenetic regulators of RNA modification has gradually become the hotspot of cancer research. Studies have shown that alteration of epigenetic modifications can promote the development and metastasis of breast cancer. This review highlights the progress in characterization of the link between RNA modification and the prognosis, carcinogenesis and treatment of breast cancer, which may provide a new theoretical basis for development of effective strategies for monitoring of breast cancer based on epigenetics.
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Affiliation(s)
| | | | | | | | | | - Xi Gu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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28
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Wang N, Huo X, Zhang B, Chen X, Zhao S, Shi X, Xu H, Wei X. METTL3-Mediated ADAMTS9 Suppression Facilitates Angiogenesis and Carcinogenesis in Gastric Cancer. Front Oncol 2022; 12:861807. [PMID: 35574388 PMCID: PMC9097454 DOI: 10.3389/fonc.2022.861807] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/22/2022] [Indexed: 01/04/2023] Open
Abstract
The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration.
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Affiliation(s)
- Nuofan Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinying Huo
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Baoguo Zhang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaoxiang Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Shuli Zhao
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xuesong Shi
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaowei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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29
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Chen Z, Hu Y, Jin L, Yang F, Ding H, Zhang L, Li L, Pan T. The Emerging Role of N6-Methyladenosine RNA Methylation as Regulators in Cancer Therapy and Drug Resistance. Front Pharmacol 2022; 13:873030. [PMID: 35462896 PMCID: PMC9022635 DOI: 10.3389/fphar.2022.873030] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/14/2022] [Indexed: 12/18/2022] Open
Abstract
N6-methyladenosine (m6A) RNA methylation has been considered the most prevalent, abundant, and conserved internal transcriptional modification throughout the eukaryotic mRNAs. Typically, m6A RNA methylation is catalyzed by the RNA methyltransferases (writers), is removed by its demethylases (erasers), and interacts with m6A-binding proteins (readers). Accumulating evidence shows that abnormal changes in the m6A levels of these regulators are increasingly associated with human tumorigenesis and drug resistance. However, the molecular mechanisms underlying m6A RNA methylation in tumor occurrence and development have not been comprehensively clarified. We reviewed the recent findings on biological regulation of m6A RNA methylation and summarized its potential therapeutic strategies in various human cancers.
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Affiliation(s)
- Zhaolin Chen
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China
| | - Ying Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Le Jin
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China
| | - Fan Yang
- Department of Clinical Medical, The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Haiwen Ding
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China
| | - Lei Zhang
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China
| | - Lili Li
- Department of Hematopathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tingting Pan
- Department of General Surgery, Diagnosis and Therapy Center of Thyroid and Breast, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China
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Liao J, Wei Y, Liang J, Wen J, Chen X, Zhang B, Chu L. Insight into the structure, physiological function, and role in cancer of m6A readers—YTH domain-containing proteins. Cell Death Dis 2022; 8:137. [PMID: 35351856 PMCID: PMC8964710 DOI: 10.1038/s41420-022-00947-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 02/24/2022] [Accepted: 03/15/2022] [Indexed: 12/14/2022]
Abstract
YT521-B homology (YTH) domain-containing proteins (YTHDF1-3, YTHDC1-2) are the most crucial part of N6-methyladenosine (m6A) readers and play a regulatory role in almost all stages of methylated RNA metabolism and the progression of various cancers. Since m6A is identified as an essential post-transcriptional type, YTH domain-containing proteins have played a key role in the m6A sites of RNA. Hence, it is of great significance to study the interaction between YTH family proteins and m6A-modified RNA metabolism and tumor. In this review, their basic structure and physical functions in RNA transcription, splicing, exporting, stability, and degradation as well as protein translation are introduced. Then we discussed the expression regulation of YTH domain-containing proteins in cancers. Furthermore, we introduced the role of the YTH family in cancer biology and systematically demonstrated their functions in various aspects of tumorigenesis and development. To provide a more institute understanding of the role of YTH family proteins in cancers, we summarized their functions and specific mechanisms in various cancer types and presented their involvement in cancer-related signaling pathways.
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31
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Xiao Q, Lei L, Ren J, Peng M, Jing Y, Jiang X, Huang J, Tao Y, Lin C, Yang J, Sun M, Tang L, Wei X, Yang Z, Zhang L. Mutant NPM1-Regulated FTO-Mediated m 6A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis. Front Oncol 2022; 12:817584. [PMID: 35211409 PMCID: PMC8862181 DOI: 10.3389/fonc.2022.817584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.
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Affiliation(s)
- Qiaoling Xiao
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Li Lei
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Jun Ren
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Meixi Peng
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yipei Jing
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Xueke Jiang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Junpeng Huang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yonghong Tao
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Can Lin
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Jing Yang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Minghui Sun
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Lisha Tang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Xingyu Wei
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Zailin Yang
- Hematology Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Ling Zhang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
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Liu Q. Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer. Front Genet 2022; 12:825109. [PMID: 35087575 PMCID: PMC8787278 DOI: 10.3389/fgene.2021.825109] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022] Open
Abstract
N6-methyladenosine (m6A) is a dynamic, reversible post-transcriptional modification, and the most common internal modification of eukaryotic messenger RNA (mRNA). Considerable evidence now shows that m6A alters gene expression, thereby regulating cell self-renewal, differentiation, invasion, and apoptotic processes. M6A methylation disorders are directly related to abnormal RNA metabolism, which may lead to tumor formation. M6A methyltransferase is the dominant catalyst during m6A modification; it removes m6A demethylase, promotes recognition by m6A binding proteins, and regulates mRNA metabolic processes. Bladder cancer (BC) is a urinary system malignant tumor, with complex etiology and high incidence rates. A well-differentiated or moderately differentiated pathological type at initial diagnosis accounts for most patients with BC. For differentiated superficial bladder urothelial carcinoma, the prognosis is normally good after surgery. However, due to poor epithelial cell differentiation, BC urothelial cell proliferation and infiltration may lead to invasive or metastatic BC, which lowers the 5-years survival rate and significantly affects clinical treatments in elderly patients. Here, we review the latest progress in m6A RNA methylation research and investigate its regulation on BC occurrence and development.
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Affiliation(s)
- Qiang Liu
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
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33
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Kong H, Sun J, Zhang W, Zhang H, Li H. Long intergenic non-protein coding RNA 1273 confers sorafenib resistance in hepatocellular carcinoma via regulation of methyltransferase 3. Bioengineered 2022; 13:3108-3121. [PMID: 35037556 PMCID: PMC8973700 DOI: 10.1080/21655979.2022.2025701] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib is a first-line agent approved for the treatment of advanced HCC. However, the frequent resistance of HCC cells to sorafenib greatly reduces its efficacy. Herein, we describe a novel long non-coding RNA (lncRNA) conferring sorafenib resistance. Long intergenic non-protein coding RNA 1273 (LINC01273) was significantly overexpressed in human HCC and sorafenib-resistant tissues, linking it to poor overall and relapse-free survival. We established sorafenib-resistant Huh7 (Huh7-SR) and SMMC-7721 (SMMC-7721-SR) cells, and found that the knockdown of LINC01273 repressed the viability, colony formation, and DNA synthesis rate of Huh7-SR and SMMC-7721-SR cells. The level of N6-methyladenosine (m6A) in sorafenib-resistant HCC cells was significantly decreased, which was rescued by LINC01273 silencing. Mechanistically, LINC01273 complementarity bound to miR-600, served as a ‘reservoir’ increasing miR-600 stability, and facilitating miR-600 targeting methyltransferase 3 (METTL3), a m6A ‘writer’, resulting in reducing METTL3 level. In addition, LINC01273 was modified with m6A, METTL3 increased LINC01273 m6A modification, followed by LINC01273 decay in the presence of YTHDF2, a m6A ‘reader’. Our findings reveal the key role of LINC01273 in sorafenib-resistant HCC cells, and targeting of the newly identified LINC01273/miR-600/METTL3 feedback regulatory axis may be a promising effective intervention for HCC patients with sorafenib resistance.
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Affiliation(s)
- Huifang Kong
- The First Ward of Hepatology Department, Fifth Medical Center of Chinese Pla General Hospital, Beijing, China
| | - Jie Sun
- Internal Medicine- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wei Zhang
- The First Ward of Hepatology Department, Fifth Medical Center of Chinese Pla General Hospital, Beijing, China
| | - Huixin Zhang
- The First Ward of Hepatology Department, Fifth Medical Center of Chinese Pla General Hospital, Beijing, China
| | - Hong Li
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
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The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation. Transl Oncol 2021; 16:101308. [PMID: 34911015 PMCID: PMC8681016 DOI: 10.1016/j.tranon.2021.101308] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/11/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022] Open
Abstract
YTHDC2 is significantly upregulated in human GC tissues, which is linked to poor prognosis. Knockout of YTHDC2 inhibits GC cell proliferation, migration and invasion. YTHDC2 enhances YAP translation in a m6A-dependent manner. YAP transcriptionally activates YTHDC2. Knockout of YTHDC2 inhibits GC tumor growth and metastasis in vivo. N6-methyladenosine (m6A) modification is the most prevalent internal modification in eukaryotic mRNA. YTH domain containing 2 (YTHDC2), a m6A binding protein, has recently been identified as a key player in human cancer. However, its contribution to gastric cancer (GC) remains unknown. Herein, we found that YTHDC2 was significantly upregulated in human GC tissues and associated with poor prognosis. CRISPR-Cas9 mediated YTHDC2 knockout notably inhibited GC cell viability, proliferation and invasion. Transcriptome analysis coupled with mechanism experiments revealed that yes-associated protein (YAP), the well-known oncogene, is the target of YTHDC2 in GC cells. Specifically, YTHDC2 recognized m6A-modified YAP mRNA at 5`-UTR, resulting in enhancing the translation efficiency of YAP, without affecting its mRNA level. In turn, YAP/TEAD directly targeted -843∼-831 region on the promoter of YTHDC2 and activated the transcription of YTHDC2, thus forming a positive regulatory loop. Further, using the xenograft tumor model, we found that knockout of YTHDC2 markedly reduced tumor size and lung metastasis nodules in vivo. And high YTHDC2 was strongly positively correlated with high YAP in clinical GC tissues. Collectively, our data demonstrate that YTHDC2 is a novel oncogene in GC, which provides the theoretical basis for the strategy of targeting YTHDC2 for GC patients.
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Chang LL, Xu XQ, Liu XL, Guo QQ, Fan YN, He BX, Zhang WZ. Emerging role of m6A methylation modification in ovarian cancer. Cancer Cell Int 2021; 21:663. [PMID: 34895230 PMCID: PMC8666073 DOI: 10.1186/s12935-021-02371-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022] Open
Abstract
m6A (N6-methyladenosine) methylation, a well-known modification in tumour epigenetics, dynamically and reversibly fine tunes the entire process of RNA metabolism. Aberrant levels of m6A and its regulators, which can predict the survival and outcomes of cancer patients, are involved in tumorigenesis, metastasis and resistance. Ovarian cancer (OC) ranks first among gynaecological tumours in the causes of death. At first diagnosis, patients with OC are usually at advanced stages owing to a lack of early biomarkers and effective targets. After treatment, patients with OC often develop drug resistance. This article reviews the recent experimental advances in understanding the role of m6A modification in OC, raising the possibility to treat m6A modification and its regulators as promising diagnostic markers and therapeutic targets for OC. ![]()
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Affiliation(s)
- Lin-Lin Chang
- Department of Pharmacy, Affiliated Tumour Hospital of Zhengzhou University, Henan Cancer Hospital, 127# Dongming Rd, Zhengzhou, 450008, Henan, China.
| | - Xia-Qing Xu
- Department of Clinical Pharmacy, Zhengzhou Central Hospital Affiliated To Zhengzhou University, Zhengzhou, China
| | - Xue-Ling Liu
- Department of Pharmacy, Affiliated Tumour Hospital of Zhengzhou University, Henan Cancer Hospital, 127# Dongming Rd, Zhengzhou, 450008, Henan, China
| | - Qian-Qian Guo
- Department of Pharmacy, Affiliated Tumour Hospital of Zhengzhou University, Henan Cancer Hospital, 127# Dongming Rd, Zhengzhou, 450008, Henan, China
| | - Yan-Nan Fan
- Department of Pharmacy, Affiliated Tumour Hospital of Zhengzhou University, Henan Cancer Hospital, 127# Dongming Rd, Zhengzhou, 450008, Henan, China
| | - Bao-Xia He
- Department of Pharmacy, Affiliated Tumour Hospital of Zhengzhou University, Henan Cancer Hospital, 127# Dongming Rd, Zhengzhou, 450008, Henan, China
| | - Wen-Zhou Zhang
- Department of Pharmacy, Affiliated Tumour Hospital of Zhengzhou University, Henan Cancer Hospital, 127# Dongming Rd, Zhengzhou, 450008, Henan, China.
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36
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Liu M, Zhao Z, Cai Y, Bi P, Liang Q, Yan Y, Xu Z. YTH domain family: potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma. Aging (Albany NY) 2021; 13:24205-24218. [PMID: 34747720 PMCID: PMC8610120 DOI: 10.18632/aging.203674] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/26/2021] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common high malignancy with insidious onset, invasive fast-growing, high recurrence rate and fatality. YTH domain family plays essential roles in development of HCC. However, the biological function of YTH domain family in HCC have not been clarified. Here, through evaluating the expression profiles of YTH domain family, we found that upregulated YTHDF1 might be more significant and valuable in development and progression of HCC. There was a strong correlation between YTHDC1, YTHDF1 and YTHDF2 and pathological stage of HCC patients. Kaplan-Meier plotter revealed that HCC patients with high level of YTHDF1 and YTHDF2 were highly related to a shorter overall survival time, and low level of YTHDF1 (p = 0.0017) has an important association with a longer progression-free survival time. Genetic alterations using cBioPortal revealed that the alteration rates of YTHDF3 were the highest. We also found that the functions of YTH domain family were linked to several cancer-associated pathways, including peptidyl-serine modification, peptidyl-tyrosine modification and negative regulation of cellular component movement. TIMER database indicated that the YTH domain family had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Ualcan databases revealed that the global methylation levels of YTHDC1 was higher in HCC patients, while YTHDF2 was lower in HCC patients. In conclusion, our findings will enhance the understanding of YTH domain family in HCC pathology, and provide novel insights into YTH-targeted therapy for HCC patients.
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Affiliation(s)
- Miaomiao Liu
- Department of Nuclear Medicine (PET-CT Central), Xiangya Hospital, Central South University, Changsha, China
| | - Zijin Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Cai
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Peng Bi
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Qiuju Liang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
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37
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Zhou W, Bai C, Long C, Hu L, Zheng Y. Construction and Characterization of Long Non-Coding RNA-Associated Networks to Reveal Potential Prognostic Biomarkers in Human Lung Adenocarcinoma. Front Oncol 2021; 11:720400. [PMID: 34513699 PMCID: PMC8430225 DOI: 10.3389/fonc.2021.720400] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is one type of the malignant tumors with high morbidity and mortality. The molecular mechanism of LUAD is still unclear. Studies demonstrate that lncRNAs play crucial roles in LUAD tumorigenesis and can be used as prognosis biomarkers. Thus, in this study, to identify more robust biomarkers of LUAD, we firstly constructed LUAD-related lncRNA-TF network and performed topological analyses for the network. Results showed that the network was a scale-free network, and some hub genes with high clinical values were identified, such as lncRNA RP11-173A16 and TF ZBTB37. Module analysis on the network revealed one close lncRNA module, which had good prognosis performance in LUAD. Furthermore, through integrating ceRNAs strategy and TF regulatory information, we identified some lncRNA-TF positive feedback loops. Prognostic analysis revealed that ELK4- and BDP1-related feedback loops were significant. Secondly, we constructed the lncRNA-m6A regulator network by merging all the high correlated lncRNA-m6A regulator pairs. Based on the network analysis results, some key m6A-related lncRNAs were identified, such as MIR497HG, FENDRR, and RP1-199J3. We also investigated the relationships between these lncRNAs and immune cell infiltration. Results showed that these m6A-related lncRNAs were high correlated with tumor immunity. All these results provide a new perspective for the diagnostic biomarker and therapeutic target identification of LUAD.
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Affiliation(s)
- Wenting Zhou
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Chen Bai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Chaojun Long
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Li Hu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yanfei Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Kumar S, Sarthi P, Mani I, Ashraf MU, Kang MH, Kumar V, Bae YS. Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH. Cells 2021; 10:2250. [PMID: 34571899 PMCID: PMC8466810 DOI: 10.3390/cells10092250] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/27/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular immunotherapy has recently emerged as a fourth pillar in cancer treatment co-joining surgery, chemotherapy and radiotherapy. Where, the discovery of immune checkpoint blockage or inhibition (ICB/ICI), anti-PD-1/PD-L1 and anti-CTLA4-based, therapy has revolutionized the class of cancer treatment at a different level. However, some cancer patients escape this immune surveillance mechanism and become resistant to ICB-therapy. Therefore, a more advanced or an alternative treatment is required urgently. Despite the functional importance of epitranscriptomics in diverse clinico-biological practices, its role in improving the efficacy of ICB therapeutics has been limited. Consequently, our study encapsulates the evidence, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which can be reformed into RNA modifying drugs (RMD). Here, we have explained the mechanism of individual RNA-modifiers (editor/writer, eraser/remover, and effector/reader) in overcoming the issues associated with high-dose antibody toxicities and drug-resistance. Moreover, we have shed light on the importance of suppressor of cytokine signaling (SOCS/CISH) and microRNAs in improving the efficacy of ICB-therapy, with brief insight on the current monoclonal antibodies undergoing clinical trials or already approved against several solid tumor and metastatic cancers. We anticipate our investigation will encourage researchers and clinicians to further strengthen the efficacy of ICB-therapeutics by considering the importance of epitranscriptomics as a personalized medicine.
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Affiliation(s)
- Sunil Kumar
- Department of Biological Sciences, Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea; (M.U.A.); (M.-H.K.)
- Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea
| | - Parth Sarthi
- University Department of Botany, M.Sc. Biotechnology, Ranchi University, Ranchi 834008, India;
| | - Indra Mani
- Department of Microbiology, Gargi College, University of Delhi, New Delhi 110049, India;
| | - Muhammad Umer Ashraf
- Department of Biological Sciences, Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea; (M.U.A.); (M.-H.K.)
- Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea
| | - Myeong-Ho Kang
- Department of Biological Sciences, Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea; (M.U.A.); (M.-H.K.)
- Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea
| | - Vishal Kumar
- Department of Pharmaceutical Science, Dayananda Sagar University, Bengaluru 560078, India;
| | - Yong-Soo Bae
- Department of Biological Sciences, Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea; (M.U.A.); (M.-H.K.)
- Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea
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