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Zhou Y, Wang F, Feng S, Li M, Zhu M. USP39 promote post-translational modifiers to stimulate the progress of cancer. Discov Oncol 2025; 16:749. [PMID: 40358671 PMCID: PMC12075731 DOI: 10.1007/s12672-025-02573-5] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.
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Affiliation(s)
- Yuli Zhou
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Fang Wang
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Siren Feng
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Mengsen Li
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570216, China.
| | - Mingyue Zhu
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
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Chen Y, Zhang J, Yang J, Zhao J, Guo X, Zhang J, Gan J, Zhao W, Chen S, Zhang X, Lin Y, Jin J. Exploring the cancerous nexus: the pivotal and diverse roles of USP39 in cancer development. Discov Oncol 2025; 16:715. [PMID: 40347416 PMCID: PMC12065690 DOI: 10.1007/s12672-025-02480-9] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 04/24/2025] [Indexed: 05/12/2025] Open
Abstract
The ubiquitin-proteasome system enables post-transcriptional protein modification and is a major pathway for the degradation of most of them in eukaryotic cells. Among these, the ubiquitin-specific protease (USP) family is the most extensively studied. As an important member of the USP family, ubiquitin-specific protease 39 (USP39) plays an essential role in RNA splicing and protein regulation. This review comprehensively summarizes the structural characteristics and molecular functions of USP39, emphasizing its pivotal role in the regulation of cellular processes. Dysregulation of USP39 is closely associated with the progression of various cancers through mechanisms such as immune evasion, modulation of oncogenic signaling pathways, and altered RNA splicing. These processes impact key aspects of cancer biology, including proliferation, metastasis, and therapy resistance, underscoring the broad implications of USP39 in tumor progression. Recent studies position USP39 as a promising target for cancer treatment. Future research should explore its upstream regulatory networks, develop small-molecule inhibitors, and evaluate its potential for precision oncology. This review integrates the latest insight into USP39, providing a foundation for its clinical application in cancer therapy.
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Affiliation(s)
- Yujing Chen
- School of Pharmacy, Guilin Medical University, Guangxi, 541199, Guilin, People's Republic of China
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Jingyi Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Institute of Integrated Traditional Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Jinfeng Yang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Jiawei Zhao
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, Guangxi, China
| | - Xiaotong Guo
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, Guangxi, China
| | - Juzheng Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, Guangxi, China
| | - Jinfeng Gan
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, Guangxi, China
| | - Weijia Zhao
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, Guangxi, China
| | - Siqi Chen
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
- Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Xinwen Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Yi Lin
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China.
- Department of Ultrasound, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
| | - Jiamin Jin
- School of Pharmacy, Guilin Medical University, Guangxi, 541199, Guilin, People's Republic of China.
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China.
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, Guangxi, China.
- Department of Ultrasound, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
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Kumar S, Basu M, Ghosh MK. E3 ubiquitin ligases and deubiquitinases in colorectal cancer: Emerging molecular insights and therapeutic opportunities. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119827. [PMID: 39187067 DOI: 10.1016/j.bbamcr.2024.119827] [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: 04/22/2024] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 08/28/2024]
Abstract
Colorectal cancer (CRC) presents ongoing challenges due to limited treatment effectiveness and a discouraging prognosis, underscoring the need for ground-breaking therapeutic approaches. This review delves into the pivotal role of E3 ubiquitin ligases and deubiquitinases (DUBs), underscoring their role as crucial regulators for tumor suppression and oncogenesis in CRC. We spotlight the diverse impact of E3 ligases and DUBs on CRC's biological processes and their remarkable versatility. We closely examine their specific influence on vital signaling pathways, particularly Wnt/β-catenin and NF-κB. Understanding these regulatory mechanisms is crucial for unravelling the complexities of CRC progression. Importantly, we explore the untapped potential of E3 ligases and DUBs as novel CRC treatment targets, discussing aspects that may guide more effective therapeutic strategies. In conclusion, our concise review illuminates the E3 ubiquitin ligases and deubiquitinases pivotal role in CRC, offering insights to inspire innovative approaches for transforming the treatment landscape in CRC.
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Affiliation(s)
- Sunny Kumar
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201 002, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, South 24 Paraganas, PIN - 743372, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201 002, India.
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Regalado CR, Balogh M. MMP9: Link between neuropathy and colorectal cancer? Front Mol Biosci 2024; 11:1451611. [PMID: 39664453 PMCID: PMC11631744 DOI: 10.3389/fmolb.2024.1451611] [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: 06/19/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
As chemotherapy is still a cornerstone of colorectal cancer (CRC) treatment, chemotherapy-induced peripheral neuropathy (CIPN) presents significant clinical challenges, affecting millions worldwide. A subset of colon cancer patients (approximately 30%) develop chronic CIPN, with detrimental, untreatable neuropathic pain symptoms. The risk factors of such intractable chronic CIPN are unknown. However, there is growing literature data investigating the intriguing interplay of neurons and cancer (cancer neuroscience). Recent data shows that this interplay might have a key role in the development and severity of CIPN. Given its vast (patho)physiological roles in both colon cancer and neuropathy, MMP9 seems to be a key factor that might drive the development of neuronal damage in colon cancer patients. This review investigates the role of matrix metalloproteinase 9 (MMP9) in linking CRC to neuropathy, aiming to uncover shared mechanisms that could offer new therapeutic targets. By synthesizing insights from a broad range of studies published over the last 20 years, we explore MMP9's involvement in CRC progression, its role in CIPN, and the interconnected pathways influencing both conditions. These studies reveal MMP9 as a pivotal mediator in ECM remodeling, inflammation, and signal transduction pathways, emphasizing its modulation by macrophages. These shared mechanisms of colon cancer and CIPN pathophysiology suggest MMP9's potential contribution to neuropathic conditions in CRC patients, positioning it as a critical factor in disease progression and a promising therapeutic target. Future research should focus on longitudinal studies to assess MMP9's impact on neuropathy outcomes in CRC patients, exploring MMP9 inhibitors, and developing targeted interventions to mitigate the detrimental symptoms of CIPN. MMP9 also seems to be a feasible driving factor in the development of chronic CIPN in colon cancer patients.
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Affiliation(s)
| | - Mihály Balogh
- Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Groningen, Netherlands
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Hu Y, Luo M. Cinobufotalin regulates the USP36/c-Myc axis to suppress malignant phenotypes of colon cancer cells in vitro and in vivo. Aging (Albany NY) 2024; 16:5526-5544. [PMID: 38517383 PMCID: PMC11006458 DOI: 10.18632/aging.205661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 01/04/2024] [Indexed: 03/23/2024]
Abstract
Ubiquitin-specific protease 36 (USP36) has been reported to exhibit oncogenic effects in various malignancies, but the function of USP36 in colon cancer progression remains indefinite. Herein, we aimed to determine the role and mechanism of USP36 in malignant phenotypes of colon cancer cells and explore the potential drug targeting USP36. Bioinformatics analyses indicated that USP36 is highly expressed and significantly related to tumor stages in colon cancer. Besides, USP36 was further up-regulated in oxaliplatin (Oxa)-resistant colon cancer cells. Colony formation, Edu staining, Transwell, wound healing, sphere formation, and CCK-8 assays were conducted and showed that the proliferation, Oxa-resistance, migration, stemness, and invasion of HCT116 cells were promoted after overexpressing USP36, while suppressed by USP36 knockdown. Mechanically, USP36 enhances c-Myc protein stabilization in HCT116 cells via deubiquitination. AutoDock tool and ubiquitin-AMC hydrolysis assay identified cinobufotalin (CBF), an anti-tumor drug, maybe a USP36 inhibitor by inhibiting its deubiquitination activity. CBF significantly prohibited proliferation, migration, invasion, and stemness of HCT116 cells and reversed Oxa-resistance, whereas enforced expression of USP36 blocked these effects. Moreover, in vivo analyses confirmed the oncogenic role of USP36 and the therapeutic potential of CBF in the malignancy of colon cancer. In conclusion, CBF may be a promising therapeutic agent for colon cancer due to its regulation of the USP36/c-Myc axis.
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Affiliation(s)
- Yongjun Hu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Ming Luo
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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Pei L, Zhao F, Zhang Y. USP43 impairs cisplatin sensitivity in epithelial ovarian cancer through HDAC2-dependent regulation of Wnt/β-catenin signaling pathway. Apoptosis 2024; 29:210-228. [PMID: 38087046 PMCID: PMC10830728 DOI: 10.1007/s10495-023-01873-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2023] [Indexed: 02/01/2024]
Abstract
Epithelial ovarian cancer (EOC) is the leading cause of cancer death all over the world. USP43 functions as a tumor promoter in various malignant cancers. Nevertheless, the biological roles and mechanisms of USP43 in EOC remain unknown. In this study, USP43 was highly expressed in EOC tissues and cells, and high expression of USP43 were associated with a poor prognosis of EOC. USP43 overexpression promoted EOC cell proliferation, enhanced the ability of migration and invasion, decreased cisplatin sensitivity and inhibited apoptosis. Knockdown of USP43 in vitro effectively retarded above malignant progression of EOC. In vivo xenograft tumors, silencing USP43 slowed tumor growth and enhanced cisplatin sensitivity. Mechanistically, USP43 inhibited HDAC2 degradation and enhanced HDAC2 protein stability through its deubiquitylation function. USP43 diminished the sensitivity of EOC cells to cisplatin through activation of the Wnt/β-catenin signaling pathway mediated by HDAC2. Taken together, the data in this study revealed the functions of USP43 in proliferation, migration, invasion, chemoresistance of EOC cells, and the mechanism of HDAC2-mediated Wnt/β-catenin signaling pathway. Thus, USP43 might serve as a potential target for the control of ovarian cancer progression.
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Affiliation(s)
- Lipeng Pei
- Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, Shenyang, People's Republic of China
| | - Feng Zhao
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, People's Republic of China
| | - Yi Zhang
- Department of Gynecology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, People's Republic of China.
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Al-Balushi E, Al Marzouqi A, Tavoosi S, Baghsheikhi AH, Sadri A, Aliabadi LS, Salarabedi MM, Rahman SA, Al-Yateem N, Jarrahi AM, Halimi A, Ahmadvand M, Abdel-Rahman WM. Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review. World J Gastrointest Oncol 2024; 16:197-213. [PMID: 38292842 PMCID: PMC10824112 DOI: 10.4251/wjgo.v16.i1.197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/05/2023] [Accepted: 12/07/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most frequent and the second most fatal cancer. The search for more effective drugs to treat this disease is ongoing. A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies. Ubiquitin-specific peptidases (USPs), the largest group of the deubiquitinase protein family, have long been implicated in various cancers. There have been numerous studies on the role of USPs in CRC; however, a comprehensive view of this role is lacking. AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC. METHODS We systematically queried the MEDLINE (via PubMed), Scopus, and Web of Science databases. RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC: Regulation of the cell cycle, apoptosis, cancer stemness, epithelial-mesenchymal transition, metastasis, DNA repair, and drug resistance. The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC. The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms. CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.
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Affiliation(s)
- Eman Al-Balushi
- College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Amina Al Marzouqi
- College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Shima Tavoosi
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan 81746-73441, Iran
| | - Amir Hossein Baghsheikhi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran 11365/4435, Iran
| | - Arash Sadri
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Leyla Sharifi Aliabadi
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Mohammad-Mahdi Salarabedi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Syed Azizur Rahman
- College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Nabeel Al-Yateem
- Department of Nursing, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Alireza Mosavi Jarrahi
- Cancer Research Centre, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Aram Halimi
- Cancer Research Centre, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Mohammad Ahmadvand
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences , Tehran 1416634793, Iran
| | - Wael M Abdel-Rahman
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
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Cui J, Guo Y, Yin T, Gou S, Xiong J, Liang X, Lu C, Peng T. USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2. Biomed Pharmacother 2023; 166:115359. [PMID: 37639742 DOI: 10.1016/j.biopha.2023.115359] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 08/31/2023] Open
Abstract
Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.
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Affiliation(s)
- Jing Cui
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yao Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tao Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shanmiao Gou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jiongxin Xiong
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xueyi Liang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chong Lu
- Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Tao Peng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Luo W, Zhang G, Wang Z, Wu Y, Xiong Y. Ubiquitin-specific proteases: Vital regulatory molecules in bone and bone-related diseases. Int Immunopharmacol 2023; 118:110075. [PMID: 36989900 DOI: 10.1016/j.intimp.2023.110075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/06/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
Stabilization of bone structure and function involves multiple cell-to-cell and molecular interactions, in which the regulatory functions of post-translational modifications such as ubiquitination and deubiquitination shouldn't be underestimated. As the largest family of deubiquitinating enzymes, the ubiquitin-specific proteases (USPs) participate in the development of bone homeostasis and bone-related diseases through multiple classical osteogenic and osteolytic signaling pathways, such as BMP/TGF-β pathway, NF-κB/p65 pathway, EGFR-MAPK pathway and Wnt/β-catenin pathway. Meanwhile, USPs may also broadly regulate regulate hormone expression level, cell proliferation and differentiation, and may further influence bone homeostasis from gene fusion and nuclear translocation of transcription factors. The number of patients with bone-related diseases is currently enormous, making exploration of their pathogenesis and targeted therapy a hot topic. Pathological increases in the levels of inflammatory mediators such as IL-1β and TNF-α lead to inflammatory bone diseases such as osteoarthritis, rheumatoid arthritis and periodontitis. While impaired body metabolism greatly increases the probability of osteoporosis. Abnormal physiological activity of bone-associated cells results in a variety of bone tumors. The regulatory role of USPs in bone-related disease has received particular attention from academics in recent studies. In this review, we focuse on the roles and mechanisms of USPs in bone homeostasis and bone-related diseases, with the expectation of informing targeted therapies in the clinic.
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Affiliation(s)
- Wenxin Luo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Guorui Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhanqi Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yingying Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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LIU J, LEUNG CT, LIANG L, WANG Y, CHEN J, LAI KP, TSE WKF. Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis. Cancers (Basel) 2022; 14:cancers14143547. [PMID: 35884607 PMCID: PMC9323628 DOI: 10.3390/cancers14143547] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary This review summarizes the current DUBs findings that correlate with the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The DUBs were further classified by their biological functions in terms of proliferation, metastasis, and apoptosis. The work provides an updated of the current findings, and could be used as a quick guide for researchers to identify target DUBs in cancers. Abstract Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers.
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Affiliation(s)
- Jiaqi LIU
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Chi Tim LEUNG
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China;
| | - Luyun LIANG
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Yuqin WANG
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Jian CHEN
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
- Correspondence: (J.C.); (W.K.F.T.); Tel.: +86-773-5895860 (J.C.); +81-92-802-4767 (W.K.F.T.)
| | - Keng Po LAI
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - William Ka Fai TSE
- Laboratory of Developmental Disorders and Toxicology, Center for Promotion of International Education and Research, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
- Correspondence: (J.C.); (W.K.F.T.); Tel.: +86-773-5895860 (J.C.); +81-92-802-4767 (W.K.F.T.)
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Disoma C, Zhou Y, Li S, Peng J, Xia Z. Wnt/β-catenin signaling in colorectal cancer: Is therapeutic targeting even possible? Biochimie 2022; 195:39-53. [DOI: 10.1016/j.biochi.2022.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/03/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
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12
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Ji Y, Lv J, Sun D, Huang Y. Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review). Int J Mol Med 2022; 49:1. [PMID: 34713301 PMCID: PMC8589460 DOI: 10.3892/ijmm.2021.5056] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common carcinomas. Although great progress has been made in recent years, CRC survival remains unsatisfactory due to high metastasis and recurrence. Understanding the underlying molecular mechanisms of CRC tumorigenesis and metastasis has become increasingly important. Recently, aberrant Wnt/β‑catenin signaling has been reported to be strongly associated with CRC tumorigenesis, metastasis and recurrence. Therefore, the Wnt/β‑catenin signaling pathway has potential value as a therapeutic target for CRC. In the present review, the dysregulation of this pathway in CRC and the promoting or suppressing function of therapeutic targets on CRC were explored. In addition, the interaction between this pathway and epithelial‑mesenchymal transition (EMT), cell stemness, mutations, metastasis‑related genes and tumor angiogenesis in CRC cells were also investigated. Numerous studies on this pathway may help identify the potential diagnostic and prognostic markers and therapeutic targets for CRC.
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Affiliation(s)
- Yong Ji
- Department of General Surgery, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, P.R. China
| | - Jian Lv
- Department of General Surgery, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, P.R. China
| | - Di Sun
- Department of General Surgery, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, P.R. China
| | - Yufeng Huang
- Department of Oncology, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, P.R. China
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13
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Jiang Z, Hou Z, Liu W, Yu Z, Liang Z, Chen S. Circular RNA protein tyrosine kinase 2 (circPTK2) promotes colorectal cancer proliferation, migration, invasion and chemoresistance. Bioengineered 2022; 13:810-823. [PMID: 34974791 PMCID: PMC8805883 DOI: 10.1080/21655979.2021.2012952] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 02/07/2023] Open
Abstract
The dysregulated circular RNAs (circRNAs) are linked to progression and chemoresistance in colorectal cancer (CRC). However, the role of circRNA protein tyrosine kinase 2 (circPTK2) in CRC progression and chemoresistance is uncertain. The circPTK2, microRNA (miR)-136-5p, m6A 'reader' protein YTH domain family protein 1 (YTHDF1), β-catenin and cyclin D1 abundances were examined via quantitative reverse transcription PCR or Western blotting. The progression was investigated by cell counting kit-8 (CCK-8), colony formation, transwell and xenograft analysis. The resistance to 5-fluorouracil (5-FU) and oxaliplatin was analyzed via detecting cell viability and apoptosis using CCK-8 analysis and flow cytometry. The binding relationship was examined through dual-luciferase reporter, RNA immunoprecipitation and pull-down analysis. In our study, circPTK2 abundance was enhanced in CRC and associated with liver metastasis, clinical stage and chemoresistance. CircPTK2 knockdown constrained cell proliferation, migration, invasion, resistance to 5-FU and oxaliplatin, and the Wnt/β-catenin signaling. MiR-136-5p was bound with circPTK2 and downregulated in CRC. MiR-136-5p knockdown attenuated the influence of circPTK2 silence on CRC progression and chemoresistance. YTHDF1 was targeted via miR-136-5p and upregulated in CRC samples and cells. MiR-136-5p targeted YTHDF1 to restrain CRC progression and chemoresistance. In addition, we confirmed that circPTK2 silence reduced xenograft tumor growth. In conclusion, circPTK2 interference suppressed CRC proliferation, migration, invasion and chemoresistance via regulating miR-136-5p and YTHDF1.Abbreviations: circRNAs: circular RNAs; CRC: colorectal cancer; circPTK2: circRNA protein tyrosine kinase 2; miR: microRNA; YTHDF1: YTH domain family protein 1; CCK-8: cell counting kit-8; 5-FU: 5-fluorouracil; RIP: RNA immunoprecipitation.
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Affiliation(s)
- Zhipeng Jiang
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China
| | - Zehui Hou
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China
| | - Wei Liu
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China
| | - Zhuomin Yu
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China
| | - Zhiqiang Liang
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China
| | - Shuang Chen
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China
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14
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Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh-Aghdaei H, Ashrafian Bonab M, Nazemalhosseini-Mojarad E, Mini E. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246226. [PMID: 34944846 PMCID: PMC8699154 DOI: 10.3390/cancers13246226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression. Abstract Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis
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Affiliation(s)
- Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Bahador Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Haniye Nazari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran 19395-1495, Iran;
| | - Hiva Soleimani
- Department of General Biology, Faculty of Fundamental Science, Islamic Azad University of Shahr-E-Qods, Tehran 37515-374, Iran;
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Maziar Ashrafian Bonab
- School of Medicine, University of Sunderland, City Campus, Chester Road, Sunderland SR1 3SD, UK;
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran
- Correspondence: (E.N.-M.); (E.M.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Correspondence: (E.N.-M.); (E.M.)
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15
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Dong X, Liu Z, Zhang E, Zhang P, Wang Y, Hang J, Li Q. USP39 promotes tumorigenesis by stabilizing and deubiquitinating SP1 protein in hepatocellular carcinoma. Cell Signal 2021; 85:110068. [PMID: 34197957 DOI: 10.1016/j.cellsig.2021.110068] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/24/2021] [Accepted: 06/24/2021] [Indexed: 01/17/2023]
Abstract
Deubiquitinating enzyme (DUB) can hydrolyze ubiquitin molecules from the protein bound with ubiquitin, and reversely regulate protein degradation. The ubiquitin-specific proteases (USP) family are cysteine proteases, which owns the largest members and diverse structure among the currently known DUB. The important roles of ubiquitin-specific peptidase39 (USP39) in cancer have been widely investigated. However, little is known about the putative de-ubiquitination function of USP39 in hepatocellular carcinoma (HCC) and the mechanisms of USP39 regulating tumor growth. Here, we used bioinformatics methods to reveal that USP39 expression is significantly upregulated in several cancer database. High expression of USP39 is correlated with poor prognosis of HCC patients. Then, we identify the specificity protein 1 (SP1), as a novel subtract of the USP39. We observe that USP39 stabilizes SP1 protein and prolongs its half-life by promoting its deubiquitylation pathway. In addition, our results show USP39 promotes cell proliferation by SP1-depenet manner in vivo and vitro. Knocking-down of USP39 promotes the cell apoptosis and arrest of the cell cycle, whereas SP1 forcefully reversed these effects. Taken together, our results suggest that USP39 participates the deubiquitylation of SP1 protein, providing new pathway for understand the upstream signaling for oncogene SP1.
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Affiliation(s)
- Xiao Dong
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Zixin Liu
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Navy Military Medical University (Second Military Medical University), Shanghai, China
| | - Encheng Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Pingzhao Zhang
- Department of Oncology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University, Changzhou, China
| | - Yuqi Wang
- Department of Oncology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University, Changzhou, China
| | - Junjie Hang
- Department of Oncology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University, Changzhou, China.
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China.
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16
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Cruz L, Soares P, Correia M. Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes. Pharmaceuticals (Basel) 2021; 14:ph14090848. [PMID: 34577547 PMCID: PMC8469789 DOI: 10.3390/ph14090848] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/20/2021] [Accepted: 08/21/2021] [Indexed: 12/14/2022] Open
Abstract
Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.
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Affiliation(s)
- Lucas Cruz
- i3S—Instituto de Investigação e Inovação Em Saúde, Universidade Do Porto, 4200-135 Porto, Portugal; (L.C.); (P.S.)
- Ipatimup—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4250-475 Porto, Portugal
- FCUP—Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Paula Soares
- i3S—Instituto de Investigação e Inovação Em Saúde, Universidade Do Porto, 4200-135 Porto, Portugal; (L.C.); (P.S.)
- Ipatimup—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4250-475 Porto, Portugal
- FCUP—Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
- Departamento de Patologia, Faculdade de Medicina da Universidade Do Porto, 4200-139 Porto, Portugal
| | - Marcelo Correia
- i3S—Instituto de Investigação e Inovação Em Saúde, Universidade Do Porto, 4200-135 Porto, Portugal; (L.C.); (P.S.)
- Ipatimup—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4250-475 Porto, Portugal
- Correspondence:
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17
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Cerrito MG, Grassilli E. Identifying Novel Actionable Targets in Colon Cancer. Biomedicines 2021; 9:biomedicines9050579. [PMID: 34065438 PMCID: PMC8160963 DOI: 10.3390/biomedicines9050579] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/10/2021] [Accepted: 05/14/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high-throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations.
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18
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Yuan J, Li X, Zhang G, Cheng W, Wang W, Lei Y, Ma Q, Song G. USP39 mediates p21-dependent proliferation and neoplasia of colon cancer cells by regulating the p53/p21/CDC2/cyclin B1 axis. Mol Carcinog 2021; 60:265-278. [PMID: 33634905 DOI: 10.1002/mc.23290] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/26/2021] [Accepted: 02/08/2021] [Indexed: 12/21/2022]
Abstract
Ubiquitin-specific protease 39 (USP39) is frequently overexpressed in a variety of cancers, and involved in the regulation of various biological processes, such as cell proliferation, cell cycle progression, apoptosis and pre-messenger RNA splicing. Nevertheless, the biological roles and mechanisms of USP39 in colon cancer remain largely unknown. In this study, we analyzed whether USP39 can be a molecular target for the treatment of colon cancer. Whilst overexpression of USP39 was detected in human colon cancer tissues and cell lines, USP39 knockdown was observed to inhibit the growth and subcutaneous tumor formation of colon cancer cells. Further analysis showed that USP39 knockdown can stabilize p21 by prolonging the half-life of p21 and by upregulating the promoter activity of p21. The RS domain and USP domain of USP39 were found to play an essential role. Additionally, our findings revealed that USP39 plays a regulatory role in the proliferation of colon cancer cells by the p53/p21/CDC2/cyclin B1 axis in a p21-dependent manner. Taken together, this study provided the theoretical basis that may facilitate the development of USP39 as a novel potential target of colon cancer therapy.
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Affiliation(s)
- Jiahui Yuan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Xiaomei Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Gongye Zhang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Weipeng Cheng
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Weiwei Wang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Yongbin Lei
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Qiujuan Ma
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Gang Song
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
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19
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Peng Y, Guo J, Sun T, Fu Y, Zheng H, Dong C, Xiong S. USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN-Induced Antiviral Immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:3167-3178. [PMID: 33127822 DOI: 10.4049/jimmunol.1901384] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 09/25/2020] [Indexed: 12/06/2024]
Abstract
Deubiquitinating enzymes (DUBs) are cysteine proteases that reverse the ubiquitination by removing ubiquitins from the target protein. The human genome encodes ∼100 potential DUBs, which can be classified into six families, influencing multiple cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. To systematically explore the role of DUBs involved in antiviral immunity, we performed an RNA interference-based screening that contains 97 human DUBs. We identified that ubiquitin-specific protease (USP) 39 expression modulates the antiviral activity, which is, to our knowledge, a previously unknown function of this enzyme. Small interfering RNA knockdown of USP39 significantly enhanced viral replication, whereas overexpression of USP39 had an opposite effect. Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK/STAT downstream of type I signaling by enhancing IFN-stimulated response elements promoter activity and expression of IFN-stimulated genes. Interestingly, USP39, previously considered not to have the deubiquitinase activity, in this study is proved to interact with STAT1 and sustain its protein level by deubiqutination. Furthermore, we found that through novel mechanism USP39 can significantly decrease K6-linked but not K48-linked ubiquitination of STAT1 for degradation. Taken together, these findings uncover that USP39 is, to our knowledge, a new deubiquitinase that positively regulates IFN-induced antiviral efficacy.
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Affiliation(s)
- Yihong Peng
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Jing Guo
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Tianle Sun
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yuxuan Fu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Hui Zheng
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Chunsheng Dong
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Sidong Xiong
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
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20
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Gâtel P, Piechaczyk M, Bossis G. Ubiquitin, SUMO, and Nedd8 as Therapeutic Targets in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1233:29-54. [PMID: 32274752 DOI: 10.1007/978-3-030-38266-7_2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ubiquitin defines a family of approximately 20 peptidic posttranslational modifiers collectively called the Ubiquitin-like (UbLs). They are conjugated to thousands of proteins, modifying their function and fate in many ways. Dysregulation of these modifications has been implicated in a variety of pathologies, in particular cancer. Ubiquitin, SUMO (-1 to -3), and Nedd8 are the best-characterized UbLs. They have been involved in the regulation of the activity and/or the stability of diverse components of various oncogenic or tumor suppressor pathways. Moreover, the dysregulation of enzymes responsible for their conjugation/deconjugation has also been associated with tumorigenesis and cancer resistance to therapies. The UbL system therefore constitutes an attractive target for developing novel anticancer therapeutic strategies. Here, we review the roles and dysregulations of Ubiquitin, SUMO, and Nedd8 pathways in tumorigenesis, as well as recent advances in the identification of small molecules targeting their conjugating machineries for potential application in the fight against cancer.
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Affiliation(s)
- Pierre Gâtel
- Equipe Labellisée Ligue Contre le Cancer, IGMM, Univ Montpellier, CNRS, Montpellier, France
| | - Marc Piechaczyk
- Equipe Labellisée Ligue Contre le Cancer, IGMM, Univ Montpellier, CNRS, Montpellier, France
| | - Guillaume Bossis
- Equipe Labellisée Ligue Contre le Cancer, IGMM, Univ Montpellier, CNRS, Montpellier, France.
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21
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Yan C, Yuan J, Xu J, Zhang G, Li X, Zhang B, Hu T, Huang X, Mao Y, Song G. Ubiquitin-specific peptidase 39 regulates the process of proliferation and migration of human ovarian cancer via p53/p21 pathway and EMT. Med Oncol 2019; 36:95. [PMID: 31637536 DOI: 10.1007/s12032-019-1308-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/27/2019] [Indexed: 12/15/2022]
Abstract
Ovarian cancer is one of the most lethal gynecological cancers; owning to its late detection and chemoresistance, understanding the pathogenesis of this malignant tumor is much critical. Previous studies have reported that ubiquitin-specific peptidase 39 (USP39) is generally overexpressed in a variety of cancers, including hepatocellular carcinoma, gastric cancer and so forth. Furthermore, USP39 is proved to be associated with the proliferation of malignant tumors. However, the function and mechanism of USP39 in ovarian cancer have not been elucidated. In the present study, we observed that USP39 was frequently overexpressed in human ovarian cancer and was highly correlated with TNM stage. Suppression of USP39 markedly inhibited the growth and migration of ovarian cancer cell lines HO-8910 and SKOV3 and induced cell cycle G2/M arrest. Moreover, knockdown of USP39 inhibited ovarian tumor growth in a xenograft model. In addition, our findings indicated that cell cycle arrest induced by USP39 knockdown might be involved in p53/p21 signaling pathway. Furthermore, we found that the depletion of USP39 inhibited the migration of ovarian cancer cells via blocking epithelial-mesenchymal transition. Taken together, these results suggest that USP39 may play vital roles in the genesis and progression and may serve as a potential biomarker for diagnosis and therapeutic target of ovarian cancer.
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Affiliation(s)
- Congcong Yan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jiahui Yuan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jiajia Xu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Gongye Zhang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Xiaomei Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Bing Zhang
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Tianhui Hu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Xiaohua Huang
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yubin Mao
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China. .,Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, 361102, China.
| | - Gang Song
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
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22
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Yan L, Yu HH, Liu YS, Wang YS, Zhao WH. Esculetin enhances the inhibitory effect of 5-Fluorouracil on the proliferation, migration and epithelial-mesenchymal transition of colorectal cancer. Cancer Biomark 2019; 24:231-240. [PMID: 30689555 DOI: 10.3233/cbm-181764] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is the most common malignant disease worldwide and thus new therapeutic approaches are needed. 5-Fluorouracil (5-FU) remains the most widely used agent to treat colorectal cancer (CRC). However, its clinical efficacy is currently limited by the development of drug resistance. Esculetin (EST), a coumarin, was found to have anti-proliferative and anti-migration activity in cancer. OBJECTIVE This research aims to evaluated the influence and possible mechanism of EST on the proliferation, migration and epithelial-mesenchymal transition of CRC cell lines. MATERIALS AND METHODS Human CRC cell lines HT-29, SW480, HCT-116, and Caco-2 were treated with various concentrations of EST (0.2, 2, 20, 200, 2000 μg/ml) or 5-FU (0.1, 1, 10, 100, 1000 μg/ml) for 48 h, and cell viability was determined by the MTT and CCK-8 assay. The motility of HCT-116 cells was detected by scratch assay. Western blot was applied to detect the protein expression. Besides, levels of Wnt3a and VEGF in HCT-116 cell culture medium supernatant were analyzed by ELISA. The anti-tumor effect was detected with HCT-116 subcutaneous tumor bearing tumor model by monitoring the tumor vomume in vivo. Finally, the tumoral expression of VEGF was measured by immunohistochemistry, and the expression of Ki67, PCNA, β-catenin, c-Myc, Cyclin D1, MMP2 and MMP7 was measured by Western blot analysis. RESULTS EST inhibited HCT-116 cell proliferation in a dose-dependent manner. Western blot analysis revealed that EST decreased the expression of Ki67, PCNA, N-cadherin, E-cadherin, vimentin, fibronectin, β-catenin, c-Myc, Cyclin D1, MMP2 and MMP7. Furthermore, EST reduced the release of Wnt3a and VEGF into HCT-116 cells culture medium. After EST treatment, the tumor volume was significant smaller than that of the control group, and the tumoral levels of VEGF were decreased. Moreover, western blot analysis indicated that the expression of Ki67, PCNA, β-catenin, c-Myc, Cyclin D1, MMP2 and MMP7 were also significantly decreased after treated with EST. In addition, in vitro and in vivo anti-tumor results demonstrated that EST combined with 5-FU could increase the inhibitory effect of 5-FU on HCT-116 cells proliferation, migration and epithelial-mesenchymal transition. CONCLUSIONS EST enhances the inhibitory effect of 5-FU on the proliferation, migration and epithelial-mesenchymal transition of CRC.
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Affiliation(s)
- Lin Yan
- Department of Oncology and Pneumology, Shandong Provincial Third Hospital, Jinan, Shandong 250031, China
| | - Hai-Hua Yu
- Department of Gastrointestinal Surgery, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China
| | - Yuan-Shui Liu
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China
| | - Yan-Sen Wang
- Department of Oncology and Pneumology, Shandong Provincial Third Hospital, Jinan, Shandong 250031, China
| | - Wen-Hua Zhao
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China
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23
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Ding K, Ji J, Zhang X, Huang B, Chen A, Zhang D, Li X, Wang X, Wang J. RNA splicing factor USP39 promotes glioma progression by inducing TAZ mRNA maturation. Oncogene 2019; 38:6414-6428. [PMID: 31332287 PMCID: PMC6756117 DOI: 10.1038/s41388-019-0888-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 06/06/2019] [Accepted: 07/03/2019] [Indexed: 01/01/2023]
Abstract
Increasing evidence demonstrates that ubiquitin specific protease 39 (USP39) plays an oncogenic role in various human tumors. Here, using expression analysis of the publicly available Oncomine database, clinical glioma patient samples, and glioma cells, we found that USP39 was overexpressed in human gliomas. Knockdown of USP39 in glioma cells demonstrated that the protein promoted cell growth, invasion and migration in vitro and in a tumor model in nude mice. To identify mediators of USP39 growth-promoting properties, we used luciferase reporter constructs under transcriptional control of various promoters specific to seven canonical cancer-associated pathways. Luciferase activity from a synthetic TEAD-dependent YAP/TAZ-responsive reporter, as a direct readout of the Hippo signaling pathway, was decreased by 92% in cells with USP39 knockdown, whereas the luciferase activities from the other six cancer pathways, including MAPK/ERK, MAPK/JNK, NFκB, Notch, TGFβ, and Wnt, remained unchanged. TAZ protein expression however was decreased independent of canonical Hippo signaling. Immunohistochemistry revealed a positive correlation between USP39 and TAZ proteins in orthotopic xenografts derived from modified glioma cells expressing USP39 shRNAs and primary human glioma samples (p < 0.05). Finally, loss of USP39 decreased TAZ pre-mRNA splicing efficiency in glioma cells in vitro, which led to reduced levels of TAZ protein. In summary, USP39 has oncogenic properties that increase TAZ protein levels by inducing maturation of its mRNA. USP39 therefore provides a novel therapeutic target for the treatment of human glioma.
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Affiliation(s)
- Kaikai Ding
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Jianxiong Ji
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Xin Zhang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Bin Huang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Anjing Chen
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Di Zhang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China
| | - Xinyu Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China. .,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China.
| | - Jian Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China. .,Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China. .,Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
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24
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Long non-coding RNA 520 is a negative prognostic biomarker and exhibits pro-oncogenic function in nasopharyngeal carcinoma carcinogenesis through regulation of miR-26b-3p/USP39 axis. Gene 2019; 707:44-52. [DOI: 10.1016/j.gene.2019.02.093] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 02/14/2019] [Accepted: 02/19/2019] [Indexed: 12/14/2022]
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25
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Liu C, Yao X, Li M, Xi Y, Zhao L. USP39 regulates the cell cycle, survival, and growth of human leukemia cells. Biosci Rep 2019; 39:BSR20190040. [PMID: 30898977 PMCID: PMC6449567 DOI: 10.1042/bsr20190040] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/03/2019] [Accepted: 03/14/2019] [Indexed: 11/17/2022] Open
Abstract
Ubiquitin-specific peptidase 39 (USP39) is one member of the cysteine proteases of the USP family, which represents the largest group of DeUbiquitinases with more than 50 members in humans. The roles of USP39 in human cancer have been widely investigated. However, the roles of USP39 in human leukemia and the underlying mechanism remain unknown. Here we reported the function of USP39 in human leukemia. We observed that the expression of USP39 was up-regulated in human leukemia cells and the high expression of USP39 was correlated with poor survival of the patients with leukemia. Lentivirus-mediated knockdown of USP39 repressed the proliferation and colony formation of human leukemia cell lines HL-60 and Jurkat cells. Mechanism study showed that USP39 knockdown induced the arrest of cell cycle and apoptosis of leukemia cells. In addition, our microarray and bioinformatic analysis demonstrated that USP39 regulated diverse cellular signaling pathways that were involved in tumor biology, and several pivotal genes (IRF1, Caspase 8, and SP1) have been validated by quantitative real-time polymerase chain reaction. Knockdown or IRF1 partially restored the proliferation rate of leukemia cells with USP39 knockdown. Taken together, our findings implicate that USP39 promotes the development of human leukemia by regulating cell cycle, survival, and proliferation of the cells.
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Affiliation(s)
- Chunxia Liu
- Department of Hematology, the First Hospital of Lanzhou University, Lanzhou 730000, P.R. China
| | - Xiaojian Yao
- Department of Hematology, the First Hospital of Lanzhou University, Lanzhou 730000, P.R. China
| | - Ming Li
- Department of Hematology, the First Hospital of Lanzhou University, Lanzhou 730000, P.R. China
| | - Yaming Xi
- Department of Hematology, the First Hospital of Lanzhou University, Lanzhou 730000, P.R. China
| | - Li Zhao
- Department of Hematology, the First Hospital of Lanzhou University, Lanzhou 730000, P.R. China
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26
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Qiao G, Dai C, He Y, Shi J, Xu C. Effects of miR‑106b‑3p on cell proliferation and epithelial‑mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma. Int J Mol Med 2019; 43:1817-1829. [PMID: 30816445 PMCID: PMC6414160 DOI: 10.3892/ijmm.2019.4107] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 02/18/2019] [Indexed: 01/15/2023] Open
Abstract
Previous studies have demonstrated that the dysregulation of microRNAs (miRs) is frequently associated with cancer progression. Deregulation of miR‑106b‑3p has been observed in various types of human cancer. However, the biological function of miR‑106b‑3p in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, the aim of this study was to investigate the role of miR‑106b‑3p in ESCC. In the current study, the results indicated that miR‑106b‑3p was upregulated in ESCC cell lines and tissues. An increase in miR‑106b‑3p using miR mimics significantly promoted the proliferation of ESCC cells in vitro. Furthermore, the results demonstrated that miR‑106b‑3p overexpression promoted migration, invasion and epithelial‑mesenchymal transition (EMT) of ESCC cells. In addition, zinc and ring finger 3 (ZNRF3) was identified as a target of miR‑106b‑3p in ESCC cells, and the ZNRF3 expression level was inversely associated with miR‑106b‑3p. It was also demonstrated that miR‑106b‑3p has a role in EMT by regulating Wnt/β‑catenin signaling pathway in ESCC. In conclusion, these data suggested that miR‑106b‑3p promotes cell proliferation and invasion, partially by downregulating ZNRF3 and inducing EMT via Wnt/β‑catenin signaling in ESCC cells. Thus, miR‑106b‑3p and ZNRF3 may be novel molecular targets for the future treatment of ESCC.
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Affiliation(s)
- Guanen Qiao
- Department of Digestion, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006
- Department of Digestive, The First Hospital of Handan City, Handan, Hebei 056002
| | - Chenguang Dai
- Department of Digestion, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006
| | - Yang He
- Hematological Disease Engineering Center of Ministry of Education, Soochow University, Suzhou, Jiangsu 215006
| | - Junjie Shi
- Department of Thoracic Surgery, The First Hospital of Handan City, Handan, Hebei 056002, P.R. China
| | - Chunfang Xu
- Department of Digestion, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006
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27
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Jiang D, Zhou B, Xiong Y, Cai H. miR-135 regulated breast cancer proliferation and epithelial-mesenchymal transition acts by the Wnt/β-catenin signaling pathway. Int J Mol Med 2019; 43:1623-1634. [PMID: 30720046 PMCID: PMC6414157 DOI: 10.3892/ijmm.2019.4081] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 01/17/2019] [Indexed: 12/23/2022] Open
Abstract
Breast cancer (BC) is the most common cancer in women around the world. microRNAs (miRNAs/miRs) have been proved to be associated with the development and progression of breast cancer. In the present study, to elucidate the effects of dysregulated miR‑135 on cells and underlying mechanisms in BC, in vitro and in vivo experiments were conducted. The biological functions of miR‑135 were studied using MTT, colony formation, wound healing, transwell assays as well as tumorigenicity analysis. Gain‑ and loss‑ of function of miR‑135 studies revealed that ectopic expression of miR‑135 in MDA‑MB‑468 and MCF‑7 cells significantly inhibited cell growth, migration, invasion and EMT, at least in part through inhibiting the activation of the Wnt/β‑catenin pathway. Moreover, this was reversed in cells which were transfected with miR‑135 inhibitors. Taken together, the results of the present study provided evidence that miR‑135 acted as a tumor suppressor in BC, which may represent a novel therapeutic strategy for the diagnosis and prognosis of BC.
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Affiliation(s)
- Daqiong Jiang
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Bo Zhou
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yan Xiong
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Hongbing Cai
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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28
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Dong X, Su H, Jiang F, Li H, Shi G, Fan L. miR-133a, directly targeted USP39, suppresses cell proliferation and predicts prognosis of gastric cancer. Oncol Lett 2018; 15:8311-8318. [PMID: 29805563 PMCID: PMC5950022 DOI: 10.3892/ol.2018.8421] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 03/02/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer has high incidence and mortality, and the mortality ranks second only to lung cancer. Downregulation of miR-133a has been observed in certain types of tumors, and it is involved in gastric cancer. The aim of the present study was to explore the molecular mechanisms of miR-133a and ubiquitin-specific protease 39 (USP39) in gastric cancer. Western blot analysis and RT-PCR were employed to measure miR-133a and USP39 expression. To confirm whether miR-133a targeted USP39, we conducted a luciferase reporter assay. We utilized 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay to detect the effects of miR-133a on gastric cell proliferation. miR-133a was significantly downregulated in cancer tissues and cell lines (HGC-27 and MGC-803), while the expression level of USP39 was higher in tumor tissues than in paracancerous tissues. Upregulated expression of miR-133a and/or USP39 downregulation could inhibit cell proliferation in gastric cancer cells. Furthermore, USP39 was identified as a direct target of miR-133a and the inverse relationship between them was also observed. USP39 was a firsthand target of miR-133a and there was a negative correlation between them. In addition, a low expression of miR-133a or overexpression of USP39 predicted poor prognosis. In conclusion, miR-133a may be a novel therapeutic target of microRNA-mediated suppression of cell proliferation in CC, but the role of the miR-133a/USP39 axis in CC progression needs further study.
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Affiliation(s)
- Xiang Dong
- Digestive System Department, Jining First People's Hospital, Jining, Shandong 272011, P.R. China
| | - Hailong Su
- Department of General Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Feng Jiang
- Department of Imaging, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
| | - Haiyan Li
- Department of Anesthesiology, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
| | - Guangwen Shi
- Department of Obstetrics, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
| | - Lijuan Fan
- Digestive System Department, Jining First People's Hospital, Jining, Shandong 272011, P.R. China
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29
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Tang X, Zha L, Li H, Liao G, Huang Z, Peng X, Wang Z. Upregulation of GNL3 expression promotes colon cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway. Oncol Rep 2017; 38:2023-2032. [PMID: 28849076 PMCID: PMC5652940 DOI: 10.3892/or.2017.5923] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 08/03/2017] [Indexed: 11/09/2022] Open
Abstract
G protein nucleolar 3 (GNL3), a nucleolar GTP-binding protein, is highly expressed in progenitor cells, stem cells, and various types of cancer cells. Therefore, it is considered to have an important role in cancer pathogenesis. GNL3 has been reported to play crucial roles in cell proliferation, cell cycle regulation, inhibition of differentiation, ribosome biogenesis, and the maintenance of stemness, genome stability and telomere integrity. Furthermore, GNL3 has recently been shown to be involved in cancer invasion and metastasis. However, the biological significance of GNL3 in the invasion and metastasis of colon cancer remains unclear. This study was performed to address this gap in knowledge. GNL3 expression was upregulated in colon cancer tissue specimens and correlated with tumor differentiation, invasion and metastasis. GNL3 overexpression promoted cell proliferation, invasion, migration and the epithelial-mesenchymal transition (EMT) in colon cancer cells. Moreover, inhibition of the EMT and the Wnt/β-catenin signaling pathway induced by GNL3 knockdown was partially reversed by lithium chloride (LiCl). Based on these data, GNL3 promotes the EMT in colon cancer by activating the Wnt/β-catenin signaling pathway. In summary, GNL3 is upregulated in colon cancer and plays an important role in tumor growth, invasion and metastasis. Strategies targeting GNL3 are potential treatments for colon cancer.
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Affiliation(s)
- Xi Tang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Lang Zha
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hui Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Gang Liao
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zhen Huang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xudong Peng
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ziwei Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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