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Li L, Zhang Z, Huang N, Ren J, Qin Y, Luo Y. IGF1R activates FOXP3-β-catenin signaling to promote breast cancer development. Breast Cancer Res Treat 2025; 211:467-478. [PMID: 40055251 DOI: 10.1007/s10549-025-07663-0] [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: 09/25/2024] [Accepted: 02/22/2025] [Indexed: 04/18/2025]
Abstract
PURPOSE Forkhead box P3 (FOXP3), a key marker of regulatory T cells (Tregs), is crucial for Treg differentiation and development. Emerging evidence suggests that FOXP3 is also expressed in various tumor cells; however, its role in tumor progression remains controversial. This study aimed to elucidate the impact of FOXP3 on breast cancer development. METHODS Breast cancer cell lines, including HCC1937, HCC1806, Hs 578T, MDA-MB-231, and MCF-7, along with xenograft mouse models, to assess the effects of FOXP3 on cell proliferation and tumor growth. FOXP3 expression in human breast cancer samples was analyzed using quantitative PCR and immunohistochemistry analyses. Cell proliferation and invasion were evaluated through MTS and transwell assays, respectively. Chromatin immunoprecipitation (ChIP) assays were performed to determine FOXP3 binding to the β-catenin gene promoter. RESULTS FOXP3 expression was elevated in advanced breast cancer and correlates with poor clinical outcomes. FOXP3 directly binds to β-catenin gene promoter - 986 to - 1168 region to facilitate β-catenin transcription, consequently resulting in increased breast cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Furthermore, IGF1R activated FOXP3-β-catenin signaling to promote breast tumor growth. Moreover, elesclomol, a potent copper ionophore, significantly inhibited FOXP3 expression to suppress breast tumor growth. CONCLUSION This study indicates that FOXP3 plays an oncogenic role in breast cancer development and suggests that targeting IGF1R-FOXP3-β-catenin signaling may be a putative therapeutic strategy for human breast cancer treatment.
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Affiliation(s)
- Lu Li
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Zhiming Zhang
- Key Laboratory of Environmental and Applied Microbiology, Key Laboratory of Environmental Microbiology of Sichuan Province, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
| | - Na Huang
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Jianlan Ren
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Yuan Qin
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
| | - Yangkun Luo
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
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2
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Guo Q, Qin H, Chen Z, Zhang W, Zheng L, Qin T. Key roles of ubiquitination in regulating critical regulators of cancer stem cell functionality. Genes Dis 2025; 12:101311. [PMID: 40034124 PMCID: PMC11875185 DOI: 10.1016/j.gendis.2024.101311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/23/2024] [Accepted: 03/07/2024] [Indexed: 03/05/2025] Open
Abstract
The ubiquitin (Ub) system, a ubiquitous presence across eukaryotes, plays a crucial role in the precise orchestration of diverse cellular protein processes. From steering cellular signaling pathways and orchestrating cell cycle progression to guiding receptor trafficking and modulating immune responses, this process plays a crucial role in regulating various biological functions. The dysregulation of Ub-mediated signaling pathways in prevalent cancers ushers in a spectrum of clinical outcomes ranging from tumorigenesis and metastasis to recurrence and drug resistance. Ubiquitination, a linchpin process mediated by Ub, assumes a central mantle in molding cellular signaling dynamics. It navigates transitions in biological cues and ultimately shapes the destiny of proteins. Recent years have witnessed an upsurge in the momentum surrounding the development of protein-based therapeutics aimed at targeting the Ub system under the sway of cancer stem cells. The article provides a comprehensive overview of the ongoing in-depth discussions regarding the regulation of the Ub system and its impact on the development of cancer stem cells. Amidst the tapestry of insights, the article delves into the expansive roles of E3 Ub ligases, deubiquitinases, and transcription factors entwined with cancer stem cells. Furthermore, the spotlight turns to the interplay with pivotal signaling pathways the Notch, Hedgehog, Wnt/β-catenin, and Hippo-YAP signaling pathways all play crucial roles in the regulation of cancer stem cells followed by the specific modulation of Ub-proteasome.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Hai Qin
- Department of Clinical Laboratory, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, Guizhou 550014, China
| | - Zelong Chen
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Artificial Intelligence and IoT Smart Medical Engineering Research Center of Henan Province, Zhengzhou, Henan 450008, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Tingting Qin
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
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Zhang Z, Cao J, Xing H, Liu J, Li L, Zhang Y. USP2-induced upregulation of LEF1 through deubiquitination relieves osteoporosis development by promoting the osteogenic differentiation of bone marrow mesenchymal stem cells. J Orthop Surg Res 2025; 20:430. [PMID: 40301985 PMCID: PMC12039128 DOI: 10.1186/s13018-025-05834-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/21/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) exhibit therapeutic potential for osteoporosis through their differentiation into osteoblasts. Here, we investigated the role and mechanism of lymphoid enhancer-binding factor 1 (LEF1) in regulating osteogenic differentiation of human BMSCs (hBMSCs). METHODS hBMSCs were exposed to the specific medium to induce their osteogenic differentiation. The ovariectomy (OVX)-induced osteoporotic mouse model was constructed. LEF1 and USP2 mRNA expression was analyzed by quantitative PCR, and protein levels were detected by immunohistochemistry and immunoblotting. Cell proliferation was assessed by CCK-8 assay. Alkaline phosphatase (ALP) expression and activity assay and Alizarin Red staining were used to evaluate osteogenic differentiation. LEF1 protein stability analysis and co-immunoprecipitation (Co-IP) assay were performed to test the USP2/LEF1 interaction. RESULTS During hBMSC osteogenic differentiation, LEF1 and USP2 levels were increased in hBMSCs. Inhibiting LEF1 or USP2 diminished the proliferation and osteogenic differentiation of hBMSCs in vitro. Mechanistically, USP2 stabilized LEF1 protein by mediating LEF1 deubiquitination. Increased expression of LEF1 reversed USP2 knockdown-imposed suppression on proliferation and osteogenic differentiation of hBMSCs. Moreover, increased USP2 expression reduced bone loss and enhanced osteogenic differentiation in OVX mice. Additionally, LEF1 and USP2 were downregulated in the bone marrow of patients with osteoporosis. CONCLUSION Our findings provide the first demonstration of the USP2/LEF1 cascade that enhances the osteogenic differentiation of hBMSCs, broadening the field for the development of BMSCs as effective agents in osteoporosis therapy.
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Affiliation(s)
- Zhihong Zhang
- Department of Orthopedics Ward 2, Kailuan General Hospital, No. 57, Xinhua East Road, Tangshan City, Hebei Province, 063000, China
| | - Jie Cao
- Department of Orthopedics Ward 2, Kailuan General Hospital, No. 57, Xinhua East Road, Tangshan City, Hebei Province, 063000, China
| | - Hanwen Xing
- Department of Hematology, Kailuan General Hospital, Tangshan City, Hebei, 063000, China
| | - Jing Liu
- Department of Operating Room, Tangshan people's hospital Guye Institute District, Tangshan City, Hebei, 063000, China
| | - Linshuo Li
- Department of Orthopedics Ward 2, Kailuan General Hospital, No. 57, Xinhua East Road, Tangshan City, Hebei Province, 063000, China
| | - Yue Zhang
- Department of Orthopedics Ward 2, Kailuan General Hospital, No. 57, Xinhua East Road, Tangshan City, Hebei Province, 063000, China.
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4
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Kim D, Nam HJ, Baek SH. Ubiquitination of transcription factors in cancer: unveiling therapeutic potential. Mol Oncol 2025. [PMID: 40227962 DOI: 10.1002/1878-0261.70033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 03/05/2025] [Accepted: 03/21/2025] [Indexed: 04/16/2025] Open
Abstract
Transcription factors, pivotal in gene expression regulation, are essential in cancer progression. Their function is meticulously regulated by post-translational modifications, including ubiquitination. This process, which marks proteins for degradation, can either enhance or inhibit the function of transcription factors, contingent on the context. In cancers, dysregulated ubiquitination of transcription factors contributes to the hallmark of uncontrolled growth and survival of tumors. For example, tumor suppressors such as p53 might be degraded prematurely due to abnormal ubiquitination, causing genomic instability. On the other hand, oncogenic transcription factors may gain stability via ubiquitination, thus facilitating tumorigenesis. Targeting the ubiquitin-proteasome system (UPS) therefore could be a viable therapeutic approach in cancer. Emerging treatments aim to block the ubiquitination of oncogenic transcription factors or to stabilize tumor suppressors. This review underscores the critical impact of transcription factor-altered ubiquitination on cancer progression. Additionally, it outlines innovative therapeutic approaches that involve inhibitors or drugs directed at specific ubiquitin E3 ligases and deubiquitinases (DUBs) that regulate transcription factor activity.
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Affiliation(s)
- Dongha Kim
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Jin Nam
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
- Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, Korea
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Korea
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Liu P, Chen Z, Guo Y, He Q, Pan C. Recent advances in small molecule inhibitors of deubiquitinating enzymes. Eur J Med Chem 2025; 287:117324. [PMID: 39908798 DOI: 10.1016/j.ejmech.2025.117324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/24/2024] [Accepted: 01/23/2025] [Indexed: 02/07/2025]
Abstract
Proteins play a pivotal role in maintaining cellular homeostasis. Their degradation primarily orchestrated through the ubiquitin-proteasome system (UPS) and cellular autophagy. Dysfunction of the UPS is associated with various human diseases, including cancer, autoimmune disorders, and neurodegenerative conditions. Consequently, the UPS has emerged as a promising therapeutic target. Deubiquitinases (DUBs) have garnered significant attention as potential targets for therapeutic intervention due to their role in modulating protein stability and function. This review focuses on recent advancements of DUBs, particularly their relevance in the UPS and their potential as drug targets. Notably, inhibitors targeting specific DUBs, such as USP1, USP7, USP14, and USP30 have shown promise in preclinical and clinical studies for cancer therapy. Additionally, DUB inhibitors have been involved in novel therapeutic approaches lately, including as targets for proteolysis-targeting chimeras (PROTACs) or as tools in deubiquitinase-targeting chimeras (DUBTACs).
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Affiliation(s)
- Pengwei Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China
| | - Zhengyang Chen
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China
| | - Yiting Guo
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China.
| | - Chenghao Pan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China.
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Chen S, Yang J, Qi G, Zhao J, Chen Y, Guo X, Zhang J, Gan J, Jian Z, Jin J. Evodiamine inhibits colorectal cancer cell stemness by disturbing ubiquitin specific protease 4 mediated SOX9 stabilization. Discov Oncol 2025; 16:403. [PMID: 40140224 PMCID: PMC11947356 DOI: 10.1007/s12672-025-02183-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second most deadly cancer worldwide. It is of great importance to explore new mechanisms and therapeutic targets. Ubiquitin-specific protease 4 (USP4), as a key regulator of protein stability, has been proven to be closely associated with cancer progression. In addition, it has been found that evodiamine, a novel alkaloid, can effectively inhibit the stemness of colorectal cancer. Based on this, in this study, we explored in depth the interaction mechanism between USP4 and evodiamine in regulating cancer stemness. Our research data showed that the expression level of USP4 in CRC tissues and cells was significantly increased. Further experiments found that overexpression of USP4 could significantly enhance the migration and invasion of CRC and promote the expression of stemness-related genes such as SOX9, OCT4, and CD133. In contrast, knockdown of USP4 expression in CRC cells had the opposite effect. Moreover, USP4 promotes the progression of CRC by mediating the deubiquitination and stabilization of SOX9 protein. At the same time, evodiamine can significantly inhibit the expression of USP4, SOX9, OCT4, and CD133 in CRC cells. Its mechanism of action lies in the fact that evodiamine disrupts the deubiquitination process of USP4 on SOX9 protein, thereby effectively inhibiting the stemness of CRC. Developing an Evodiamine derivative will provide new approach for improving the outcome of CRC patients.
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Affiliation(s)
- Siqi Chen
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, People's Republic of China
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Jinfeng Yang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Department of Immunology, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Guangying Qi
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Jiawei Zhao
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Yujing Chen
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- School of Pharmacy, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Xiaotong Guo
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Juzheng Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Jinfeng Gan
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199, People's Republic of China
| | - Zhiyuan Jian
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, People's Republic of China.
| | - Jiamin Jin
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, People's Republic of China.
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People's Republic of China.
- School of Pharmacy, Guilin Medical University, Guilin, 541199, People's Republic of China.
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199, People's Republic of China.
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Xie Z, Lin H, Wu Y, Yu Y, Liu X, Zheng Y, Wang X, Wu J, Xu M, Han Y, Zhang Q, Deng Y, Lin L, Linzhu Y, Qingyun L, Lin X, Huang Y, Chi P. USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer. Cell Death Dis 2025; 16:81. [PMID: 39922805 PMCID: PMC11807140 DOI: 10.1038/s41419-025-07424-3] [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: 07/03/2024] [Revised: 01/14/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to identify potential genes associated with the autophagy panel and assess their prognostic significance, biological roles, and mechanisms in CRC metastasis. Among the candidates, CENPF emerged as the top gene in our screening process. We found that CENPF expression was preferentially elevated in CRC tissues compared to adjacent normal tissues, with significantly higher levels in CRC patients with tumor recurrence. Furthermore, a multicenter cohort study demonstrated that upregulated CENPF expression was strongly associated with poorer disease-free survival in CRC. Functional experiments showed that CENPF knockdown inhibited CRC cell invasion and metastasis both in vitro and in vivo. Intriguingly, we found CENPF undergoes degradation in CRC via the ubiquitination-proteasome pathway. Mechanistically, we observed that USP4 interacted with and stabilized CENPF via deubiquitination. Furthermore, USP4-mediated CENPF upregulation was critical regulators of metastasis of CRC. Examination of clinical samples confirmed that USP4 expression positively correlates with CENPF protein expression, but not mRNA transcript levels. Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.
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Affiliation(s)
- Zhongdong Xie
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hanbin Lin
- Central Laboratory, Affiliated Hospital of Putian University, Putian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Yuecheng Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Yanan Yu
- Guilin Medical University, Guilin, China
| | - Xintong Liu
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yating Zheng
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaojie Wang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Jiashu Wu
- Department of Science and Technology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Meifang Xu
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yuting Han
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Qiongying Zhang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu Deng
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yan Linzhu
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Li Qingyun
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Xinjian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
| | - Ying Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
| | - Pan Chi
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
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Bakkar M, Khalil S, Bhayekar K, Kushwaha ND, Samarbakhsh A, Dorandish S, Edwards H, Dou QP, Ge Y, Gavande NS. Ubiquitin-Specific Protease Inhibitors for Cancer Therapy: Recent Advances and Future Prospects. Biomolecules 2025; 15:240. [PMID: 40001543 PMCID: PMC11853158 DOI: 10.3390/biom15020240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Cancer management has traditionally depended on chemotherapy as the mainstay of treatment; however, recent advancements in targeted therapies and immunotherapies have offered new options. Ubiquitin-specific proteases (USPs) have emerged as promising therapeutic targets in cancer treatment due to their crucial roles in regulating protein homeostasis and various essential cellular processes. This review covers the following: (1) the structural and functional characteristics of USPs, highlighting their involvement in key cancer-related pathways, and (2) the discovery, chemical structures, mechanisms of action, and potential clinical implications of USP inhibitors in cancer therapy. Particular attention is given to the role of USP inhibitors in enhancing cancer immunotherapy, e.g., modulation of the tumor microenvironment, effect on regulatory T cell function, and influence on immune checkpoint pathways. Furthermore, this review summarizes the current progress and challenges of clinical trials involving USP inhibitors as cancer therapy. We also discuss the complexities of achieving target selectivity, the ongoing efforts to develop more specific and potent USP inhibitors, and the potential of USP inhibitors to overcome drug resistance and synergize with existing cancer treatments. We finally provide a perspective on future directions in targeting USPs, including the potential for personalized medicine based on specific gene mutations, underscoring their significant potential for enhancing cancer treatment. By elucidating their mechanisms of action, clinical progress, and potential future applications, we hope that this review could serve as a useful resource for both basic scientists and clinicians in the field of cancer therapeutics.
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Affiliation(s)
- Mohamad Bakkar
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI 48201, USA; (M.B.); (K.B.); (N.D.K.); (A.S.); (S.D.)
- Division of Pediatric Hematology and Oncology, Children’s Hospital of Michigan, Detroit, MI 48201, USA
| | - Sara Khalil
- Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.K.); (Q.P.D.)
| | - Komal Bhayekar
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI 48201, USA; (M.B.); (K.B.); (N.D.K.); (A.S.); (S.D.)
| | - Narva Deshwar Kushwaha
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI 48201, USA; (M.B.); (K.B.); (N.D.K.); (A.S.); (S.D.)
| | - Amirreza Samarbakhsh
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI 48201, USA; (M.B.); (K.B.); (N.D.K.); (A.S.); (S.D.)
| | - Sadaf Dorandish
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI 48201, USA; (M.B.); (K.B.); (N.D.K.); (A.S.); (S.D.)
| | - Holly Edwards
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA;
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute (KCI), Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Q. Ping Dou
- Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.K.); (Q.P.D.)
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA;
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute (KCI), Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Yubin Ge
- Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.K.); (Q.P.D.)
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA;
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute (KCI), Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Navnath S. Gavande
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI 48201, USA; (M.B.); (K.B.); (N.D.K.); (A.S.); (S.D.)
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute (KCI), Wayne State University School of Medicine, Detroit, MI 48201, USA
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9
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Li F, Zhou Y, Lin X, Zhang Y, Hu Q, Zhao E, Li H, Pan X, Shu F, Zhang K, Huang C, Tang N, Liao W. A novel USP4 inhibitor that suppresses colorectal cancer stemness by promoting β-catenin and Twist1 degradation. J Transl Med 2025; 23:114. [PMID: 39856683 PMCID: PMC11762077 DOI: 10.1186/s12967-024-06001-0] [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: 09/17/2024] [Accepted: 12/13/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND The high mortality rate of metastatic colorectal cancer (CRC) is primarily attributed to resistance to chemotherapy, where cancer stem cells (CSCs) play a crucial role. Deubiquitinating enzymes are essential regulators of CSC maintenance, making them potential targets for eliminating CSCs and overcoming chemotherapy resistance. This study aims to identify key deubiquitinating enzymes regulating CSCs and drug resistance of CRC. METHODS RNA sequencing was performed to examine the mRNA expression of known deubiquitinating enzymes in CRC tissues from patients with alternate response to chemotherapy. Gain- and loss-of-function experiments were performed to evaluate the function of USP4 in regulation of stemness and drug sensitivity in CRC. High-throughput virtual screening and target management assays were conducted to identify small molecule inhibitor targeting USP4. Cell lines, organoids and animal models were used to evaluate the function of USP4 and its small molecule inhibitor in stemness and chemotherapy response. RESULTS The expression of USP4 was significantly elevated in CRC samples from progressive disease (PD) or stable disease (SD) patients compared to partial response (PR) specimen. USP4 promoted stemness by stabilizing the β-catenin and Twist1 proteins in CRC cells. A natural small molecule product U4-I05 diminished the stem-like features of CSCs and enhanced their sensitivity to oxaliplatin and 5-fluorouracil by targeting inhibition of its deubiquitinating enzyme activity through binding the catalytic domain of USP4 (311 cysteine site) at nanomolar concentrations, triggering proteasome-mediated degradation of β-catenin and Twist1. Treatment with U4-I05 also inhibited tumor metastasis and extended survival in a genetically engineered CRC mouse model. CONCLUSIONS This study identifies U4-I05 as a USP4 inhibitor with significant therapeutic efficacy against CRC, offering a promising avenue for the development of new treatments targeting cancer stemness and chemotherapy resistance.
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Affiliation(s)
- Fengtian Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China
- The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Yi Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Xinyue Lin
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China
- The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Yaxin Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Qingyong Hu
- School of Basic Medical Sciences and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Enen Zhao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Huali Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Xingyan Pan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Feng Shu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Kun Zhang
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China
- The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Chengmei Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
| | - Na Tang
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Wenting Liao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
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10
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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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11
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Xian Y, Ye J, Tang Y, Zhang N, Peng C, Huang W, He G. Deubiquitinases as novel therapeutic targets for diseases. MedComm (Beijing) 2024; 5:e70036. [PMID: 39678489 PMCID: PMC11645450 DOI: 10.1002/mco2.70036] [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: 07/10/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 12/17/2024] Open
Abstract
Deubiquitinating enzymes (DUBs) regulate substrate ubiquitination by removing ubiquitin or cleaving within ubiquitin chains, thereby maintaining cellular homeostasis. Approximately 100 DUBs in humans counteract E3 ubiquitin ligases, finely balancing ubiquitination and deubiquitination processes to maintain cellular proteostasis and respond to various stimuli and stresses. Given their role in modulating ubiquitination levels of various substrates, DUBs are increasingly linked to human health and disease. Here, we review the DUB family, highlighting their distinctive structural characteristics and chain-type specificities. We show that DUB family members regulate key signaling pathways, such as NF-κB, PI3K/Akt/mTOR, and MAPK, and play crucial roles in tumorigenesis and other diseases (neurodegenerative disorders, cardiovascular diseases, inflammatory disorders, and developmental diseases), making them promising therapeutic targets Our review also discusses the challenges in developing DUB inhibitors and underscores the critical role of the DUBs in cellular signaling and cancer. This comprehensive analysis enhances our understanding of the complex biological functions of the DUBs and underscores their therapeutic potential.
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Affiliation(s)
- Yali Xian
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Jing Ye
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Yu Tang
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine ResourcesSchool of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine ResourcesSchool of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine ResourcesSchool of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Gu He
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
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12
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Frolov A, Atwood SG, Guzman MA, Martin JR. A Rare Case of Polymicrogyria in an Elderly Individual With Unique Polygenic Underlining. Cureus 2024; 16:e74300. [PMID: 39717325 PMCID: PMC11665267 DOI: 10.7759/cureus.74300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2024] [Indexed: 12/25/2024] Open
Abstract
Polymicrogyria (PMG) is the most common malformation of cortical development (MCD) and presents as an irregularly patterned cortical surface with numerous small gyri and shallow sulci leading to various neurological deficits including developmental delays, intellectual disability, epilepsy, and language and motor issues. The presentation of PMG varies and is often found in conjunction with other congenital anomalies. Histologically, PMG features an abnormal cortical structure and dyslamination, resulting in its classification as a defect of neuronal migration and organization. Due in part to a variety of etiologies, little is known about the molecular mechanism(s) underlining PMG. To address this gap in knowledge, a case study is presented where an elderly individual with a medical history of unspecified PMG was examined postmortem by using a combination of anatomical, magnetic resonance imaging (MRI), histopathological, and genetic techniques. The results of the study allowed the classification of this case as bifrontal PMG. The genetic screening by whole exome sequencing (WES) on the Illumina Next Generation Sequencing (NGS) platform yielded 83 rare (minor allele frequency, MAF ≤ 0.01) pathological/deleterious variants where none of the respective genes has been previously linked to PMG. However, a subsequent analysis of those variants revealed that a significant number of affected genes were associated with most of the biological processes known to be impaired in PMG thereby pointing toward a polygenic nature in the present case. One of the notable features of the WES dataset was the presence of rare pathological/deleterious variants of genes (ADGRA2, PCDHA1, PCDHA12, PTK7, TPGS1, and USP4) involved in the regulation of Wnt signaling potentially highlighting the latter as an important PMG contributor in the present case. Notably, ADGRA2 warrants a closer look as a candidate gene for PMG because it not only regulates cortical patterning but has also been recently linked to two cases of bifrontal PMG with multiple congenital anomalies through its compound heterozygous mutations.
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Affiliation(s)
- Andrey Frolov
- Department of Surgery - Center for Anatomical Science and Education, Saint Louis University School of Medicine, St. Louis, USA
| | - Stuart G Atwood
- Department of Surgery - Center for Anatomical Science and Education, Saint Louis University School of Medicine, St. Louis, USA
| | - Miguel A Guzman
- Department of Pathology, Saint Louis University School of Medicine, St. Louis, USA
| | - John R Martin
- Department of Surgery - Center for Anatomical Science and Education, Saint Louis University School of Medicine, St. Louis, USA
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13
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Hu C, Zhang W, Jia Y, Zhao J, Chen Q, Hao C, Yu Y. USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway. Aging (Albany NY) 2024; 16:12850-12865. [PMID: 39393052 PMCID: PMC11501377 DOI: 10.18632/aging.206108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 07/29/2024] [Indexed: 10/13/2024]
Abstract
Ubiquitin-specific protease 4 (USP4) has been identified as a promising oncogenic factor implicated in various human malignancies. However, the exact biological functions and underlying mechanisms of USP4 in the progression of papillary thyroid carcinoma (PTC) remain elusive. In this study, we observed a marked upregulation of USP4 expression in PTC tumor tissues. Elevated levels of USP4 were significantly correlated with aggressive clinicopathological features and poor prognosis. Functional assays for loss-of-function demonstrated that silencing USP4 hindered the proliferation of PTC cells. Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells. Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways. In summary, our findings elucidate the critical involvement of the USP4/LDHA axis in driving PTC progression through the modulation of MAPK and AKT pathways, thereby identifying USP4 as a potential therapeutic target for the treatment of PTC.
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Affiliation(s)
- Chuanxiang Hu
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wei Zhang
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yongsheng Jia
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jimin Zhao
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Qian Chen
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Chengfei Hao
- Department of Hepatopancreatobiliary Surgery, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Yang Yu
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
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14
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Hong Z, Liu F, Zhang Z. Ubiquitin modification in the regulation of tumor immunotherapy resistance mechanisms and potential therapeutic targets. Exp Hematol Oncol 2024; 13:91. [PMID: 39223632 PMCID: PMC11367865 DOI: 10.1186/s40164-024-00552-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Although immune checkpoint-based cancer immunotherapy has shown significant efficacy in various cancers, resistance still limits its therapeutic effects. Ubiquitination modification is a mechanism that adds different types of ubiquitin chains to proteins, mediating protein degradation or altering their function, thereby affecting cellular signal transduction. Increasing evidence suggests that ubiquitination modification plays a crucial role in regulating the mechanisms of resistance to cancer immunotherapy. Drugs targeting ubiquitination modification pathways have been shown to inhibit tumor progression or enhance the efficacy of cancer immunotherapy. This review elaborates on the mechanisms by which tumor cells, immune cells, and the tumor microenvironment mediate resistance to cancer immunotherapy and the details of how ubiquitination modification regulates these mechanisms, providing a foundation for enhancing the efficacy of cancer immunotherapy by intervening in ubiquitination modification.
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Affiliation(s)
- Zihang Hong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Organ Transplantation, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, China.
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15
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Samuel VP, Moglad E, Afzal M, Kazmi I, Alzarea SI, Ali H, Almujri SS, Abida, Imran M, Gupta G, Chinni SV, Tiwari A. Exploring Ubiquitin-specific proteases as therapeutic targets in Glioblastoma. Pathol Res Pract 2024; 260:155443. [PMID: 38981348 DOI: 10.1016/j.prp.2024.155443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/24/2024] [Accepted: 06/28/2024] [Indexed: 07/11/2024]
Abstract
Glioblastoma (GB) remains a formidable challenge and requires new treatment strategies. The vital part of the Ubiquitin-proteasome system (UPS) in cellular regulation has positioned it as a potentially crucial target in GB treatment, given its dysregulation oncolines. The Ubiquitin-specific proteases (USPs) in the UPS system were considered due to the garden role in the cellular processes associated with oncolines and their vital function in the apoptotic process, cell cycle regulation, and autophagy. The article provides a comprehensive summary of the evidence base for targeting USPs as potential factors for neoplasm treatment. The review considers the participation of the UPS system in the development, resulting in the importance of p53, Rb, and NF-κB, and evaluates specific goals for therapeutic administration using midnight proteasomal inhibitors and small molecule antagonists of E1 and E2 enzymes. Despite the slowed rate of drug creation, recent therapeutic discoveries based on USP system dynamics hold promise for specialized therapies. The review concludes with an analysis of future wanderers and the feasible effects of targeting USPs on personalized GB therapies, which can improve patient hydration in this current and unattractive therapeutic landscape. The manuscript emphasizes the possibility of USP oncogene therapy as a promising alternative treatment line for GB. It stresses the direct creation of research on the medical effectiveness of the approach.
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Affiliation(s)
- Vijaya Paul Samuel
- Department of Anatomy, RAK College of Medicine, RAK Medical and Health Sciences University, Ras Al Khaimah, the United Arab Emirates
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Al-Jouf, Saudi Arabia
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Salem Salman Almujri
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Aseer 61421, Saudi Arabia
| | - Abida
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome-Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Suresh V Chinni
- Department of Biochemistry, Faculty of Medicine, Bioscience, and Nursing, MAHSA University, Jenjarom, Selangor 42610, Malaysia
| | - Abhishek Tiwari
- Department of Pharmacy, Pharmacy Academy, IFTM University, Lodhipur-Rajpur, Moradabad 244102, India.
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16
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Xu Y, Yu Y, Yan R, Ke X, Qu Y. Modulating β-catenin homeostasis for cancer therapy. Trends Cancer 2024; 10:507-518. [PMID: 38521655 DOI: 10.1016/j.trecan.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 02/05/2024] [Accepted: 02/26/2024] [Indexed: 03/25/2024]
Abstract
β-Catenin is a well-established driver of many cancers; however, there are challenges in developing agents targeting β-catenin for clinical use. Recent progress has indicated that most of the pathological changes in β-catenin may be commonly caused by loss of protein homeostasis. Modulation of β-catenin homeostasis, especially by hyperactivation of β-catenin, potentially leads to robust antitumor outcomes. Here, we comprehensively dissect the protein homeostasis of β-catenin in terms of time, compartmentalization, supramolecular assemblies, and dynamics, with emphasis on changes in β-catenin homeostasis upon oncogenic mutations. We propose that altered β-catenin homeostasis could be deleterious for β-catenin-dependent cancers and that modulation of β-catenin homeostasis offers a novel avenue for targeting β-catenin for cancer therapy.
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Affiliation(s)
- Yu Xu
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Ying Yu
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Rong Yan
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Xisong Ke
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
| | - Yi Qu
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
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17
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Tsukiyama T. New insights in ubiquitin-dependent Wnt receptor regulation in tumorigenesis. In Vitro Cell Dev Biol Anim 2024; 60:449-465. [PMID: 38383910 PMCID: PMC11126518 DOI: 10.1007/s11626-024-00855-w] [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: 10/24/2023] [Accepted: 01/17/2024] [Indexed: 02/23/2024]
Abstract
Wnt signaling plays a crucial role in embryonic development and homeostasis maintenance. Delicate and sensitive fine-tuning of Wnt signaling based on the proper timings and positions is required to balance cell proliferation and differentiation and maintain individual health. Therefore, homeostasis is broken by tissue hypoplasia or tumor formation once Wnt signal dysregulation disturbs the balance of cell proliferation. The well-known regulatory mechanism of Wnt signaling is the molecular reaction associated with the cytoplasmic accumulation of effector β-catenin. In addition to β-catenin, most Wnt effector proteins are also regulated by ubiquitin-dependent modification, both qualitatively and quantitatively. This review will explain the regulation of the whole Wnt signal in four regulatory phases, as well as the different ubiquitin ligases and the function of deubiquitinating enzymes in each phase. Along with the recent results, the mechanism by which RNF43 negatively regulates the surface expression of Wnt receptors, which has recently been well understood, will be detailed. Many RNF43 mutations have been identified in pancreatic and gastrointestinal cancers and examined for their functional alteration in Wnt signaling. Several mutations facilitate or activate the Wnt signal, reversing the RNF43 tumor suppressor function into an oncogene. RNF43 may simultaneously play different roles in classical multistep tumorigenesis, as both wild-type and mutant RNF43 suppress the p53 pathway. We hope that the knowledge obtained from further research in RNF43 will be applied to cancer treatment in the future despite the fully unclear function of RNF43.
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Affiliation(s)
- Tadasuke Tsukiyama
- Department of Biochemistry, Graduate School of Medicine, Hokkaido University, 15NW7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
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18
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Zhou Y, Li H, Zhang Y, Zhao E, Huang C, Pan X, Shu F, Liu Z, Tang N, Li F, Liao W. Deubiquitinase USP4 suppresses antitumor immunity by inhibiting IRF3 activation and tumor cell-intrinsic interferon response in colorectal cancer. Cancer Lett 2024; 589:216836. [PMID: 38556105 DOI: 10.1016/j.canlet.2024.216836] [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: 01/07/2024] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 04/02/2024]
Abstract
Despite the approval of immune checkpoint blockade (ICB) therapy for various tumor types, its effectiveness is limited to only approximately 15% of patients with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) colorectal cancer (CRC). Approximately 80%-85% of CRC patients have a microsatellite stability (MSS) phenotype, which features a rare T-cell infiltration. Thus, elucidating the mechanisms underlying resistance to ICB in patients with MSS CRC is imperative. In this study, we demonstrate that ubiquitin-specific peptidase 4 (USP4) is upregulated in MSS CRC tumors and negatively regulates the immune response against tumors in CRC. Additionally, USP4 represses the cellular interferon (IFN) response and antigen presentation and impairs PRR signaling-mediated cell death. Mechanistically, USP4 impedes the nuclear localization of interferon regulator Factor 3 (IRF3) by deubiquitinating the K63-polyubiquitin chain of TRAF6 and IRF3. Knockdown of USP4 enhances the infiltration of T cells in CRC tumors and overcomes ICB resistance in an MC38 syngeneic mouse model. Moreover, published datasets revealed that patients showing higher USP4 expression exhibited decreased responsiveness to anti-PD-L1 therapy. These findings highlight an essential role of USP4 in the suppression of antitumor immunity in CRC.
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Affiliation(s)
- Yi Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Huali Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Yaxin Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Enen Zhao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Chengmei Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Xingyan Pan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Feng Shu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Zhihao Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Na Tang
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Fengtian Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; School of Biosciences and Technology, Chengdu Medical College, Chengdu, 610500, Sichuan, China.
| | - Wenting Liao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
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Cui Z, Cong M, Yin S, Li Y, Ye Y, Liu X, Tang J. Role of protein degradation systems in colorectal cancer. Cell Death Discov 2024; 10:141. [PMID: 38485957 PMCID: PMC10940631 DOI: 10.1038/s41420-023-01781-8] [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: 07/18/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 03/18/2024] Open
Abstract
Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy-lysosome system are the two primary pathways responsible for protein degradation and directly related to cell survival. In malignant tumors, the UPS plays a critical role in managing the excessive protein load caused by cancer cells hyperproliferation. In this review, we provide a comprehensive overview of the dual roles played by the UPS and autolysosome system in colorectal cancer (CRC), elucidating their impact on the initiation and progression of this disease while also highlighting their compensatory relationship. Simultaneously targeting both protein degradation pathways offers new promise for enhancing treatment efficacy against CRC. Additionally, apoptosis is closely linked to ubiquitination and autophagy, and caspases degrade proteins. A thorough comprehension of the interplay between various protein degradation pathways is highly important for clarifying the mechanism underlying the onset and progression of CRC.
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Affiliation(s)
- Zihan Cui
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Mingqi Cong
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Shengjie Yin
- Department of Oncology, Chifeng City Hospital, Chifeng, 024000, China
| | - Yuqi Li
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Yuguang Ye
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
| | - Xi Liu
- Cardiovascular Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China.
| | - Jing Tang
- Department of Pathology, Harbin Medical University, Harbin, 150081, China.
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Wei H, Li X, Liu F, Li Y, Luo B, Huang X, Chen H, Wen B, Ma P. Curcumin inhibits the development of colorectal cancer via regulating the USP4/LAMP3 pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1749-1762. [PMID: 37728623 DOI: 10.1007/s00210-023-02721-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023]
Abstract
In this study, we aimed to explore the effects of curcumin on the progression of colorectal cancer and its underlying mechanisms involved. Cell proliferation, apoptosis and invasion were determined through CCK-8 assay, colony formation assay, EdU assay, flow cytometry, and transwell invasion assay, respectively. The protein expression of Bax, MMP2, USP4 and LAMP3 was measured using western blot. Pearson correlation coefficient was used to evaluate the relationship between USP4 and LAMP3. Co-IP was also conducted to determine the interaction between USP4 and LAMP3. Xenograft tumor model was established to explore the role of curcumin in colorectal cancer in vivo. IHC was utilized to measure the expression of Bax, MMP2, USP4 and LAMP3 in tumor tissues from mice. Curcumin significantly accelerated cell apoptosis, and inhibited cell proliferation and invasion in LoVo and HCT-116 cells. LAMP3 was augmented in colorectal cancer tissues and cells, and curcumin could reduce the expression of LAMP3. Curcumin decreased LAMP3 expression to exhibit the inhibition role in the progression of colorectal cancer. USP4 interacted with LAMP3, and positively regulated LAMP3 expression in colorectal cancer cells. LAMP3 overexpression could reverse the suppressive effects of USP4 knockdown on the development of colorectal cancer. Curcumin downregulated USP4 to impeded the progression of colorectal cancer via repressing LAMP3 expression. In addition, curcumin obviously restrained tumor growth in mice through downregulating USP4 and LAMP3 expression. These data indicated that curcumin exert the anti-tumor effects on the development of colorectal cancer through modulating the USP4/LAMP3 pathway.
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Affiliation(s)
- Hai Wei
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Xianzhe Li
- Department of General Surgery, Nanshi Hospital, Nanyang, 473065, China
| | - Fu Liu
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Yuan Li
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Bin Luo
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Xin Huang
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Hang Chen
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Bo Wen
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Pei Ma
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China.
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21
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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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Ren J, Yu P, Liu S, Li R, Niu X, Chen Y, Zhang Z, Zhou F, Zhang L. Deubiquitylating Enzymes in Cancer and Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303807. [PMID: 37888853 PMCID: PMC10754134 DOI: 10.1002/advs.202303807] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/30/2023] [Indexed: 10/28/2023]
Abstract
Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein-protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus-faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi-faced roles of DUBs in cancer and immunity.
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Affiliation(s)
- Jiang Ren
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Peng Yu
- Zhongshan Institute for Drug DiscoveryShanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP. R. China
| | - Sijia Liu
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouP. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceHangzhou310058China
| | - Ran Li
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Xin Niu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Yan Chen
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Zhenyu Zhang
- Department of NeurosurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450003P. R. China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Long Zhang
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouP. R. China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
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23
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Wang Q, Chen F, Yang N, Xu L, Yu X, Wu M, Zhou Y. DEPDC1B-mediated USP5 deubiquitination of β-catenin promotes breast cancer metastasis by activating the wnt/β-catenin pathway. Am J Physiol Cell Physiol 2023; 325:C833-C848. [PMID: 37642235 PMCID: PMC10635659 DOI: 10.1152/ajpcell.00249.2023] [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: 06/06/2023] [Revised: 08/18/2023] [Accepted: 08/18/2023] [Indexed: 08/31/2023]
Abstract
Breast cancer has become the malignant disease with the highest morbidity and mortality among female cancer patients. The prognosis of metastatic breast cancer is very poor, and the therapeutic effects still need to be improved. The molecular mechanism of breast cancer has not been fully clarified. Bioinformatics analysis was used to find the differentially expressed gene that affects the occurrence and development of breast cancer. Furthermore, scratch assays, Transwell assays, immunofluorescence, and Western blotting were used to determine the biological behavior of breast cancer cells affected by DEP domain-containing protein 1B (DEPDC1B). The molecular mechanism was investigated by mass spectrometry analysis, coimmunoprecipitation, and ubiquitin assays. Here, we found that DEPDC1B was highly expressed in breast cancer cells and tissues and was associated with lower overall survival (OS) in patients. We found that DEPDC1B interference significantly inhibited tumor invasion and migration in vitro and tumor metastasis in vivo. Mechanistically, DEPDC1B was first shown to activate the wnt/β-catenin signaling pathway as an oncogene in breast cancer cells. In addition, we also confirmed the interaction between DEPDC1B, ubiquitin-specific protease 5 (USP5), and β-catenin. Then, we found that DEPDC1B mediates the deubiquitination of β-catenin via USP5, which promotes cell invasion and migration. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be considered a potential therapeutic target for breast cancer.NEW & NOTEWORTHY By using bioinformatics analysis and the experimental techniques of cell biology and molecular biology, we found that DEP domain-containing protein 1B (DEPDC1B) can promote the invasion and migration of breast cancer cells and that DEPDC1B mediates the deubiquitination of β-catenin by ubiquitin-specific protease 5 (USP5), thus activating the wnt/β-catenin pathway. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be used as a potential therapeutic target for breast cancer.
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Affiliation(s)
- Qingqing Wang
- Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumour Biological Behaviours, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Department of Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Fengxia Chen
- Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumour Biological Behaviours, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Ningning Yang
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lu Xu
- Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumour Biological Behaviours, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Xiaoyan Yu
- Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumour Biological Behaviours, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Meng Wu
- Department of Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yunfeng Zhou
- Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumour Biological Behaviours, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
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Tung CH, Wu JE, Huang MF, Wang WL, Wu YY, Tsai YT, Hsu XR, Lin SH, Chen YL, Hong TM. Ubiquitin-specific peptidase 5 facilitates cancer stem cell-like properties in lung cancer by deubiquitinating β-catenin. Cancer Cell Int 2023; 23:207. [PMID: 37726816 PMCID: PMC10510149 DOI: 10.1186/s12935-023-03059-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Lung cancer has the highest mortality rate in the world, and mounting evidence suggests that cancer stem cells (CSCs) are associated with poor prognosis, recurrence, and metastasis of lung cancer. It is urgent to identify new biomarkers and therapeutic targets for targeting lung CSCs. METHODS We computed the single-sample gene set enrichment analysis (ssGSEA) of 1554 Reactome gene sets to identify the mRNA expression-based stemness index (mRNAsi)-associated pathways using the genome-wide RNA sequencing data of 509 patients from The Cancer Genome Atlas (TCGA) cohort of lung adenocarcinoma (LUAD). Phenotypic effects of ubiquitin-specific peptidase 5 (USP5) on the CSC-like properties and metastasis were examined by in vitro sphere formation assay, migration assay, invasion assay, and in vivo xenografted animal models. Cycloheximide chase assay, co-immunoprecipitation assay, and deubiquitination assay were performed to confirm the effect of USP5 on the deubiquitination of β-catenin. RESULTS We demonstrated that USP5 expression were positively correlated with the stemness-associated signatures and poor outcomes in lung cancer specimens. Silencing of endogenous USP5 reduced CSC-like characteristics, epithelial-mesenchymal transition (EMT), and metastasis in vitro and in vivo. Furthermore, USP5 interacted with β-catenin, which resulted in deubiquitination, stabilization of β-catenin, and activation of Wnt/β-catenin pathway. Accordingly, expression of USP5 was positively correlated with the enrichment score of the Wnt/TCF pathway signature in human lung cancer. Silencing of β-catenin expression suppressed USP5-enhancing sphere formation. Targeting USP5 with the small molecule WP1130 promoted the degradation of β-catenin, and showed great inhibitory effects on sphere formation, migration, and invasion. Finally, we identified a poor-prognosis subset of tumors characterized by high levels of USP5, Wnt signaling score, and Stemness score in both TCGA-LUAD and Rousseaux_2013 datasets. CONCLUSIONS These findings reveal a clinical evidence for USP5-enhanced Wnt/β-catenin signaling in promoting lung cancer stemness and metastasis, implying that targeting USP5 could provide beneficial effects to improve lung cancer therapeutics.
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Affiliation(s)
- Chia-Hao Tung
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
| | - Jia-En Wu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
| | - Meng-Fan Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
| | - Wen-Lung Wang
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Ying Wu
- Clinical Medicine Research Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Tsung Tsai
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Xiu-Rui Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
| | - Sheng-Hsiang Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
- Biostatistics Consulting Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yuh-Ling Chen
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Tse-Ming Hong
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan.
- Clinical Medicine Research Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
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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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26
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Lin YC, Zheng G, Liu HT, Wang P, Yuan WQ, Zhang YH, Peng XS, Li GJ, Wu YF, Shen HY. USP7 promotes the osteoclast differentiation of CD14+ human peripheral blood monocytes in osteoporosis via HMGB1 deubiquitination. J Orthop Translat 2023; 40:80-91. [PMID: 37333461 PMCID: PMC10275958 DOI: 10.1016/j.jot.2023.05.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/20/2023] Open
Abstract
Background Abnormal osteoclast and osteoblast differentiation is an essential pathological process in osteoporosis. As an important deubiquitinase enzyme, ubiquitin-specific peptidase 7 (USP7) participates in various disease processes through posttranslational modification. However, the mechanism by which USP7 regulates osteoporosis remains unknown. Herein, we aimed to investigate whether USP7 regulates abnormal osteoclast differentiation in osteoporosis. Methods The gene expression profiles of blood monocytes were preprocessed to analyze the differential expression of USP genes. CD14+ peripheral blood mononuclear cells (PBMCs) were isolated from whole blood collected from osteoporosis patients (OPs) and healthy donors (HDs), and the expression pattern of USP7 during the differentiation of CD14+ PBMCs into osteoclasts was detected by western blotting. The role of USP7 in the osteoclast differentiation of PBMCs treated with USP7 siRNA or exogenous rUSP7 was further investigated by the F-actin assay, TRAP staining and western blotting. Moreover, the interaction between high-mobility group protein 1 (HMGB1) and USP7 was investigated by coimmunoprecipitation, and the regulation of the USP7-HMGB1 axis in osteoclast differentiation was further verified. Osteoporosis in ovariectomized (OVX) mice was then studied using the USP7-specific inhibitor P5091 to identify the role of USP7 in osteoporosis. Results The bioinformatic analyses and CD14+ PBMCs from osteoporosis patients confirmed that the upregulation of USP7 was associated with osteoporosis. USP7 positively regulates the osteoclast differentiation of CD14+ PBMCs in vitro. Mechanistically, USP7 promoted osteoclast formation by binding to and deubiquitination of HMGB1. In vivo, P5091 effectively attenuates bone loss in OVX mice. Conclusion We demonstrate that USP7 promotes the differentiation of CD14+ PBMCs into osteoclasts via HMGB1 deubiquitination and that inhibition of USP7 effectively attenuates bone loss in osteoporosis in vivo.The translational potential of this article:The study reveals novel insights into the role of USP7 in the progression of osteoporosis and provides a new therapeutic target for the treatment of osteoporosis.
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Affiliation(s)
- Yu-Cong Lin
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Hua-Tao Liu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Wei-Quan Yuan
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Yun-Hui Zhang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Xiao-Shuai Peng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Guo-Jian Li
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Yan-Feng Wu
- Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Hui-Yong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
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27
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Ming H, Li B, Jiang J, Qin S, Nice EC, He W, Lang T, Huang C. Protein degradation: expanding the toolbox to restrain cancer drug resistance. J Hematol Oncol 2023; 16:6. [PMID: 36694209 PMCID: PMC9872387 DOI: 10.1186/s13045-023-01398-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 01/01/2023] [Indexed: 01/25/2023] Open
Abstract
Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.
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Affiliation(s)
- Hui Ming
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Jingwen Jiang
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Siyuan Qin
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Weifeng He
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Military Medical University, Chongqing, 400038, China.
| | - Tingyuan Lang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, People's Republic of China. .,Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, People's Republic of China.
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
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Pan Y, Tang Y, Gu H, Ge W. Ubiquitin modification in osteogenic differentiation and bone formation: From mechanisms to clinical significance. Front Cell Dev Biol 2022; 10:1033223. [PMID: 36340031 PMCID: PMC9634082 DOI: 10.3389/fcell.2022.1033223] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/10/2022] [Indexed: 01/03/2024] Open
Abstract
The ubiquitin-proteasome system is an important pathway for mediating posttranslational modification and protein homeostasis and exerts a wide range of functions in diverse biological processes, including stem cell differentiation, DNA repair, and cell cycle regulation. Many studies have shown that ubiquitination modification plays a critical role in regulating the osteogenic differentiation of stem cells and bone formation through various mechanisms. This review summarizes current progress on the effects and mechanisms of ubiquitin modification on transcription factors and signaling pathways involved in osteogenic differentiation. Moreover, the review highlights the latest advances in the clinical application of drugs in bone tissue engineering. A thorough understanding of ubiquitin modifications may provide promising therapeutic targets for stem cell-based bone tissue engineering.
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Affiliation(s)
- Yuan Pan
- Department of General Dentistry II, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Yiman Tang
- Fourth Clinical Division, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Hang Gu
- Department of General Dentistry II, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Wenshu Ge
- Department of General Dentistry II, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
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29
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Kaushal K, Kim EJ, Tyagi A, Karapurkar JK, Haq S, Jung HS, Kim KS, Ramakrishna S. Genome-wide screening for deubiquitinase subfamily identifies ubiquitin-specific protease 49 as a novel regulator of odontogenesis. Cell Death Differ 2022; 29:1689-1704. [PMID: 35273362 PMCID: PMC9433428 DOI: 10.1038/s41418-022-00956-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022] Open
Abstract
Proteins expressed by the paired box gene 9 (PAX9) and Msh Homeobox 1 (MSX1) are intimately involved in tooth development (odontogenesis). The regulation of PAX9 and MSX1 protein turnover by deubiquitinating enzymes (DUBs) plausibly maintain the required levels of PAX9 and MSX1 during odontogenesis. Herein, we used a loss-of-function CRISPR-Cas9-mediated DUB KO library kit to screen for DUBs that regulate PAX9 and MSX1 protein levels. We identify and demonstrate that USP49 interacts with and deubiquitinates PAX9 and MSX1, thereby extending their protein half-lives. On the other hand, the loss of USP49 reduces the levels of PAX9 and MSX1 proteins, which causes transient retardation of odontogenic differentiation in human dental pulp stem cells and delays the differentiation of human pluripotent stem cells into the neural crest cell lineage. USP49 depletion produced several morphological defects during tooth development, such as reduced dentin growth with shrunken enamel space, and abnormal enamel formation including irregular mineralization. In sum, our results suggest that deubiquitination of PAX9 and MSX1 by USP49 stabilizes their protein levels to facilitate successful odontogenesis.
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Affiliation(s)
- Kamini Kaushal
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea
| | - Eun-Jung Kim
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, South Korea
| | - Apoorvi Tyagi
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea
| | | | - Saba Haq
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 04763, South Korea
| | - Han-Sung Jung
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, South Korea.
| | - Kye-Seong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea. .,College of Medicine, Hanyang University, Seoul, 04763, South Korea.
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea. .,College of Medicine, Hanyang University, Seoul, 04763, South Korea.
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30
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Kim JM, Yang YS, Xie J, Lee O, Kim J, Hong J, Boldyreff B, Filhol O, Chun H, Greenblatt MB, Gao G, Shim JH. Regulation of sclerostin by the SIRT1 stabilization pathway in osteocytes. Cell Death Differ 2022; 29:1625-1638. [PMID: 35169297 PMCID: PMC9345882 DOI: 10.1038/s41418-022-00952-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 11/09/2022] Open
Abstract
Osteocytes play a critical role in bone remodeling through the secretion of paracrine factors regulating the differentiation and activity of osteoblasts and osteoclasts. Sclerostin is a key osteocyte-derived factor that suppresses bone formation and promotes bone resorption, therefore regulators of sclerostin secretion are a likely source of new therapeutic strategies for treatment of skeletal disorders. Here, we demonstrate that protein kinase CK2 (casein kinase 2) controls sclerostin expression in osteocytes via the deubiquitinase ubiquitin-specific peptidase 4 (USP4)-mediated stabilization of Sirtuin1 (SIRT1). Deletion of CK2 regulatory subunit, Csnk2b, in osteocytes (Csnk2bDmp1) results in low bone mass due to elevated levels of sclerostin. This phenotype in Csnk2bDmp1 mice was partly reversed when sclerostin expression was downregulated by a single intravenous injection with bone-targeting adeno-associated virus 9 (AAV9) carrying an artificial-microRNA that targets Sost. Mechanistically, CK2-induced phosphorylation of USP4 is important for stabilization of SIRT1 by suppressing ubiquitin-dependent proteasomal degradation. Upregulated expression of SIRT1 inhibits sclerostin transcription in osteocytes. Collectively, the CK2-USP4-SIRT1 pathway is crucial for the regulation of sclerostin expression in osteocytes to maintain bone homeostasis.
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Affiliation(s)
- Jung-Min Kim
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Yeon-Suk Yang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Jun Xie
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01605, USA
- Viral Vector Core, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Oksun Lee
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - JiHea Kim
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Jaehyoung Hong
- Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | | | - Odile Filhol
- Interdisciplinary Research Institute of Grenoble, IRIG-Biosanté, University Grenoble Alpes, CEA, UMR 1292, F-38000, Grenoble, France
| | - Hyonho Chun
- Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Matthew B Greenblatt
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, 10065, USA
- Hospital for Special Surgery, New York, NY, 10021, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01605, USA
- Viral Vector Core, University of Massachusetts Medical School, Worcester, MA, 01605, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Jae-Hyuck Shim
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
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Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma. Biomedicines 2022; 10:biomedicines10071531. [PMID: 35884836 PMCID: PMC9312792 DOI: 10.3390/biomedicines10071531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30–60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment modalities and higher recurrence rates. The drug resistance observed is associated with multiple genetic or epigenetic factors. The ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) is a GTPase-activating protein that functions as a deubiquitinating enzyme and regulates endocytosis and signal transduction. It is highly expressed in many cancer types and may promote the growth and proliferation of cancer cells. We hypothesized that USP6NL affects GBM chemoresistance and tumorigenesis, and that its inhibition may be a novel therapeutic strategy for GBM treatment. The USP6NL level, together with EGFR expression in human GBM tissue samples and cell lines associated with therapy resistance, tumor growth, and cancer invasion, were investigated. Its pivotal roles and potential mechanism in modulating tumor growth, and the key mechanism associated with therapy resistance of GBM cells, were studied, both in vitro and in vivo. Herein, we found that deubiquitinase USP6NL and growth factor receptor EGFR were strongly associated with the oncogenicity and resistance of GBM, both in vitro and in vivo, toward temozolomide, as evidenced by enhanced migration, invasion, and acquisition of a highly invasive and drug-resistant phenotype by the GBM cells. Furthermore, abrogation of USP6NL reversed the properties of GBM cells and resensitized them toward temozolomide by enhancing autophagy and reducing the DNA damage repair response. Our results provide novel insights into the probable mechanism through which USP6NL/EGFR signaling might suppress the anticancer therapeutic response, induce cancer invasiveness, and facilitate reduced sensitivity to temozolomide treatment in GBM in an autolysosome-dependent manner. Therefore, controlling the USP6NL may offer an alternative, but efficient, therapeutic strategy for targeting and eradicating otherwise resistant and recurrent phenotypes of aggressive GBM cells.
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Li K, Wang Q, Bian H, Chen Z, He H, Zhao X, Gong P. Comprehensive Analysis Reveals USP45 as a Novel Putative Oncogene in Pan-Cancer. Front Mol Biosci 2022; 9:886904. [PMID: 35836933 PMCID: PMC9273912 DOI: 10.3389/fmolb.2022.886904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/06/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Deubiquitinating enzymes specifically removes ubiquitin molecules from ubiquitin-tagged target proteins, thereby inhibiting the degradation of target proteins and playing an important role in tumor. However, the mechanism of deubiquitinating enzyme USP45 in tumors remains unclear. Methods: Based on the RNA-seq data of tissues and cell lines in The Cancer Genome Atlas (TCGA) database, GTEx and CCLE database, the pan-cancer analysis of USP45 expression and survival outcome were performed using R software and Kaplan-Meier Plotter. The structural variants, gene mutations and gene copy number alteration of USP45 were analyzed using the TCGA Pan-Cancer Atlas Studies dataset in the cBioPortal database. The relationships between USP45 and mRNA methylation, tumor heterogeneity, tumor stemness, and tumor immunity were performed by Sangerbox platform and TIMER2.0 using Pearson correlation analysis. Through the ENCORI database and string database, we constructed the ceRNA regulatory mechanism and protein-protein interaction network for USP45. Based on the RNA-seq data in TCGA and GTEx databases, we also constructed the downstream regulatory network for USP45 using the Limma and ClusterProfiler packages of R software. At last, the protein expression levels of USP45 were detected by immunohistochemistry in tumor tissue microarrays. Results: USP45 is upregulated in most types of tumors and negatively correlated with the overall survival and recurrence-free survival of patient. Furthermore, the structural variation, gene mutations and gene copy number variation of USP45 were identified in different types of tumors. The pan-cancer analysis showed that USP45 was closely related to mRNA methylation, tumor heterogeneity and tumor stemness. In most types of tumors, the expression of USP45 was positively correlated with many immune checkpoint molecules and immune regulators such as PD-L1, while negatively correlated with the infiltration levels of NK cells, Th1 cells, macrophages, and dendritic cells in the tumor microenvironment. Finally, we constructed the ceRNA regulatory network, protein-protein interaction network and downstream regulatory network for USP45 in different types of tumors. Conclusion: Our study firstly explored the putative oncogenic role of USP45 in pan-cancer, and provided insights for further investigation of USP45.
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Affiliation(s)
- Kai Li
- Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, China
| | - Qian Wang
- Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, China
| | - Hua Bian
- Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, China
| | - Zhiguo Chen
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Haifa He
- Department of Pathology, Central Hospital of Nanyang City, Nanyang, China
| | - Xulin Zhao
- Department of Oncology, The First People’s Hospital of Nanyang, Nanyang, China
| | - Pengju Gong
- The University of Texas MD Anderson Cancer Center UThealth Graduate School of Biomedical Sciences, Houston, TX, United States
- *Correspondence: Pengju Gong,
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Zhong C, Dong Y, Zhang Q, Yuan C, Duan S. Aberrant Expression of miR-1301 in Human Cancer. Front Oncol 2022; 11:789626. [PMID: 35070996 PMCID: PMC8767067 DOI: 10.3389/fonc.2021.789626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/13/2021] [Indexed: 12/03/2022] Open
Abstract
miR-1301 is a newly discovered miRNA, which is abnormally expressed in 14 types of tumors. miR-1301 inhibits 23 target genes, forms a ceRNA network with 2 circRNAs and 8 lncRNAs, and participates in 6 signaling pathways, thereby affecting tumor cell proliferation, invasion, metastasis, apoptosis, angiogenesis, etc. Abnormal expression of miR-1301 is often associated with poor prognosis of cancer patients. In addition, miR-1301 is related to the anti-tumor effect of epirubicin on osteosarcoma and imatinib on chronic myeloid leukemia(CML) and can enhance the cisplatin sensitivity of ovarian cancer. This work systematically summarizes the abnormal expression and prognostic value of miR-1301 in a variety of cancers, depicts the miR-1301-related signaling pathways and ceRNA network, and provides potential clues for future miR-1301 research.
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Affiliation(s)
- Chenming Zhong
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, China.,Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Yiyao Dong
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Qiudan Zhang
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Chunhui Yuan
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, China
| | - Shiwei Duan
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, China.,Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China.,Institute of Translational Medicine, Zhejiang University City College, Hangzhou, China
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USP49-mediated histone H2B deubiquitination regulates HCT116 cell proliferation through MDM2-p53 axis. Mol Cell Biol 2022; 42:e0043421. [PMID: 35072515 DOI: 10.1128/mcb.00434-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Post-translational histone modifications play important roles in regulating chromatin structure and transcriptional regulation. Histone H2B monoubiquitination (H2Bub) is an essential regulator for transcriptional elongation and ongoing transcription. Here we reported that USP49, as a histone H2B deubiquitinase, is involved in HCT116 cell proliferation through modulating MDM2-p53 pathway genes. USP49 knockout contributes to increased HCT116 cell proliferation and migration. Importantly, USP49 knockout stimulated MDM2 transcriptional level and then inhibited the mRNA levels of TP53 target genes. Conversely, overexpression of USP49 suppressed MDM2 gene expression and then promoted TP53 target genes. Moreover, chromatin immunoprecipitation revealed that USP49 directly bound to the promoter of MDM2 gene. USP49 knockout increased the H2Bub enrichment at MDM2 gene whereas USP49 overexpression downregulated the H2Bub level at MDM2 gene. Therefore, our findings indicated that USP49-mediated H2B deubiquitination controls the transcription of MDM2-p53 axis genes in the process of HCT116 cell proliferation.
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35
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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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36
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Hou X, Xia J, Feng Y, Cui L, Yang Y, Yang P, Xu X. USP47-Mediated Deubiquitination and Stabilization of TCEA3 Attenuates Pyroptosis and Apoptosis of Colorectal Cancer Cells Induced by Chemotherapeutic Doxorubicin. Front Pharmacol 2021; 12:713322. [PMID: 34630087 PMCID: PMC8495243 DOI: 10.3389/fphar.2021.713322] [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: 05/22/2021] [Accepted: 09/10/2021] [Indexed: 12/31/2022] Open
Abstract
The ubiquitin–proteasome system regulates a variety of cellular processes including growth, differentiation and apoptosis. While E1, E2, and E3 are responsible for the conjugation of ubiquitin to substrates, deubiquitinating enzymes (DUBs) reverse the process to remove ubiquitin and edit ubiquitin chains, which have profound effects on substrates’ degradation, localization, and activities. In the present study, we found that the deubiquitinating enzyme USP47 was markedly decreased in primary colorectal cancers (CRC). Its reduced expression was associated with shorter disease-free survival of CRC patients. In cultured CRC cells, knockdown of USP47 increased pyroptosis and apoptosis induced by chemotherapeutic doxorubicin. We found that USP47 was able to bind with transcription elongation factor a3 (TCEA3) and regulated its deubiquitination and intracellular level. While ectopic expression of USP47 increased cellular TCEA3 and resistance to doxorubicin, the effect was markedly attenuated by TCEA3 knockdown. Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.
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Affiliation(s)
- Xiaodan Hou
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China
| | - Jun Xia
- Department of Emergency Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuan Feng
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China
| | - Long Cui
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yili Yang
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.,China Regional Research Centre, International Centre of Genetic Engineering and Biotechnology, Taizhou, China
| | - Peng Yang
- Department of Emergency Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Xu
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.,China Regional Research Centre, International Centre of Genetic Engineering and Biotechnology, Taizhou, China
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37
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Smith R, Nadella S, Moccia R, Seymour C, Mothersill C. Copper uptake in adult rainbow trout irradiated during early life stages and in non-irradiated bystander trout which swam with the irradiated fish. Int J Radiat Biol 2021; 98:1130-1138. [PMID: 34524940 DOI: 10.1080/09553002.2021.1980627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE This investigation forms part of a wider study into the legacy effects of exposure of rainbow trout eggs 38 h after fertilization, eyed eggs, yolk sac larvae (YSL) or first feeders to a single 0.5 Gy X-ray dose, including the induction of a bystander effect, by the irradiated fish, to non-irradiated fish. Fish may be exposed to multiple environmental stressors, including waterborne metals, during their lifespan and, while there are data on how the legacy of early life stage irradiation and bystander effect induction is affected by waterborne aluminum and cadmium, there are no studies into the effects radiation or the radiation induced bystander effect on metal uptake. Therefore the aim of this investigation was to determine if the legacy of early life stage irradiation included an effect on copper uptake by adult fish and by non-irradiated bystander adult trout which swam with the irradiated fish. METHODS The four early life stages mentioned above were exposed to a single 0.5 Gy X-ray dose and then maintained, for two years with no further irradiation. At two years old the irradiated fish were allowed to swim, for 2 h with non-irradiated bystander trout (also two years old). After this time copper uptake was determined using 64Cu. RESULTS Copper uptake was increased in adult trout irradiated as eggs at 48 h after fertilization and as first feeders but eyed egg or YSL irradiation had no effect. Copper uptake was also increased in the bystander trout which swam with trout irradiated as eggs at 48 h after fertilization and as eyed eggs but there was no effect on non-irradiated adult trout which swam with trout irradiated as YSL or first feeders. CONCLUSIONS When put in context with the proteomic changes observed in these fish we propose the increased copper uptake in adult trout irradiated as eggs at 48 h after fertilization could be part of an anti-tumorigenic response and the increase in copper uptake in adult trout irradiated as first feeders could be part of a potentially protective pro-apoptotic response. Similarly we propose the increase in copper uptake in non-irradiated adult trout, induced by trout irradiated as eggs at 48 h after fertilization or as eyed eggs, was part of the universally anti-tumorigenic nature of the X-ray induced bystander effect in fish. However this was exclusive to embryonic irradiation.
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Affiliation(s)
- Richard Smith
- Department of Animal Biosciences, University of Guelph, Guelph, Canada
| | - Sunita Nadella
- Department of Biology, McMaster University, Hamilton, Canada
| | - Richard Moccia
- Department of Animal Biosciences, University of Guelph, Guelph, Canada
| | - Colin Seymour
- Department of Biology, McMaster University, Hamilton, Canada
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Snyder NA, Silva GM. Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response. J Biol Chem 2021; 297:101077. [PMID: 34391779 PMCID: PMC8424594 DOI: 10.1016/j.jbc.2021.101077] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/17/2022] Open
Abstract
Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein-protein interaction, posttranslational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.
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Affiliation(s)
- Nathan A Snyder
- Department of Biology, Duke University, Durham, North Carolina, USA
| | - Gustavo M Silva
- Department of Biology, Duke University, Durham, North Carolina, USA.
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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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Han L, Guo T, Liu DL, Tan YY. Progress in research of deubiquitination enzymes in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2021; 29:809-815. [DOI: 10.11569/wcjd.v29.i14.809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Liu Han
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China,Research Center of Digestive Diseases, Central South University, Changsha 410011, Hunan Province, China
| | - Ting Guo
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China,Research Center of Digestive Diseases, Central South University, Changsha 410011, Hunan Province, China
| | - De-Liang Liu
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China,Research Center of Digestive Diseases, Central South University, Changsha 410011, Hunan Province, China
| | - Yu-Yong Tan
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China,Research Center of Digestive Diseases, Central South University, Changsha 410011, Hunan Province, China
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Hariri H, St-Arnaud R. Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts. Int J Mol Sci 2021; 22:ijms22147746. [PMID: 34299363 PMCID: PMC8304380 DOI: 10.3390/ijms22147746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/12/2021] [Accepted: 07/16/2021] [Indexed: 11/16/2022] Open
Abstract
The ubiquitin-proteasome system regulates biological processes in normal and diseased states. Recent investigations have focused on ubiquitin-dependent modifications and their impacts on cellular function, commitment, and differentiation. Ubiquitination is reversed by deubiquitinases, including ubiquitin-specific peptidases (USPs), whose roles have been widely investigated. In this review, we explore recent findings highlighting the regulatory functions of USPs in osteoblasts and providing insight into the molecular mechanisms governing their actions during bone formation. We also give a brief overview of our work on USP53, a target of PTH in osteoblasts and a regulator of mesenchymal cell lineage fate decisions. Emerging evidence addresses questions pertaining to the complex layers of regulation exerted by USPs on osteoblast signaling. We provide a short overview of our and others' understanding of how USPs modulate osteoblastogenesis. However, further studies using knockout mouse models are needed to fully understand the mechanisms underpinning USPs actions.
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Affiliation(s)
- Hadla Hariri
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada;
- Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0C7, Canada
| | - René St-Arnaud
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada;
- Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0C7, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 1A4, Canada
- Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 1A1, Canada
- Correspondence: ; Tel.: +514-282-7155; Fax: +514-842-5581
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Guo JN, Xia BR, Deng SH, Yang C, Pi YN, Cui BB, Jin WL. Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential. Front Cell Dev Biol 2021; 9:680100. [PMID: 34179009 PMCID: PMC8220152 DOI: 10.3389/fcell.2021.680100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/17/2021] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.
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Affiliation(s)
- Jun-Nan Guo
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bai-Rong Xia
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Anhui Provincial Cancer Hospital, University of Science and Technology of China, Hefei, China
| | - Shen-Hui Deng
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chang Yang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ya-Nan Pi
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wei-Lin Jin
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Institute of Cancer Neuroscience, The First Clinical Medical College of Lanzhou University, Lanzhou, China
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Li Y, Zhou J. USP5 Promotes Uterine Corpus Endometrial Carcinoma Cell Growth and Migration via mTOR/4EBP1 Activation. Cancer Manag Res 2021; 13:3913-3924. [PMID: 34012297 PMCID: PMC8128349 DOI: 10.2147/cmar.s290467] [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: 11/09/2020] [Accepted: 04/15/2021] [Indexed: 12/30/2022] Open
Abstract
Background Uterine corpus endometrial carcinoma (UCEC) is a common malignancy worldwide developed in the female reproductive system, which can be life-threatening due to metastasis and poor prognosis. Deubiquitinating enzymes (DUBs) play key roles in ubiquitin–proteasome system. As a member of DUBs, the ubiquitin-specific protease 5 (USP5) has been found to be an oncogene in several cancers. This study aims to explore the function of USP5 in UCEC. Materials and Methods Clinical significance of USP5 was assessed from The Cancer Genome Atlas (TCGA) UCEC dataset. Knockdown and overexpression were performed by transfecting the cells with siRNAs and pCDNA3.1 vectors, respectively. CCK8, colony formation, wound healing, transwell, PI, and PI/annexin V staining were conducted to check the effect of USP5 on cellular biology function. Western blot assay was used to detect protein expression. Results USP5 was upregulated in UCEC patients. Its downregulation led to decreased migration and proliferation of UCEC cells, and meanwhile, cell cycle arrest and apoptosis were induced. By contrast, USP5 overexpression significantly promoted cell migration and cell mitosis. Further study revealed that USP5 could cause hyperactivation of mTOR/4EBP1 pathway and rapamycin treatment could totally reverse the effects of UPS5 overexpression. Conclusion Our data demonstrated that USP5 functioned as an oncogene in UCEC, which provided new insights into the pathogenesis of UCEC and a promising molecular target for UCEC diagnosis and therapy.
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Affiliation(s)
- Yinghua Li
- The Third Departments of Gynecological Oncology, Hunan Cancer Hospital, Changsha, 410013, Hunan, People's Republic of China
| | - Jian Zhou
- The Third Departments of Gynecological Oncology, Hunan Cancer Hospital, Changsha, 410013, Hunan, People's Republic of China
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The Multifaceted Roles of USP15 in Signal Transduction. Int J Mol Sci 2021; 22:ijms22094728. [PMID: 33946990 PMCID: PMC8125482 DOI: 10.3390/ijms22094728] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.
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Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors. Int J Mol Sci 2021; 22:ijms22094546. [PMID: 33925279 PMCID: PMC8123678 DOI: 10.3390/ijms22094546] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/03/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors.
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Hu B, Zhang D, Zhao K, Wang Y, Pei L, Fu Q, Ma X. Spotlight on USP4: Structure, Function, and Regulation. Front Cell Dev Biol 2021; 9:595159. [PMID: 33681193 PMCID: PMC7935551 DOI: 10.3389/fcell.2021.595159] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 01/15/2021] [Indexed: 02/05/2023] Open
Abstract
The deubiquitinating enzyme (DUB)–mediated cleavage of ubiquitin plays a critical role in balancing protein synthesis and degradation. Ubiquitin-specific protease 4 (USP4), a member of the largest subfamily of cysteine protease DUBs, removes monoubiquitinated and polyubiquitinated chains from its target proteins. USP4 contains a DUSP (domain in USP)–UBL (ubiquitin-like) domain and a UBL-insert catalytic domain, sharing a common domain organization with its paralogs USP11 and USP15. USP4 plays a critical role in multiple cellular and biological processes and is tightly regulated under normal physiological conditions. When its expression or activity is aberrant, USP4 is implicated in the progression of a wide range of pathologies, especially cancers. In this review, we comprehensively summarize the current knowledge of USP4 structure, biological functions, pathological roles, and cellular regulation, highlighting the importance of exploring effective therapeutic interventions to target USP4.
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Affiliation(s)
- Binbin Hu
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Dingyue Zhang
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Kejia Zhao
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Wang
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lijiao Pei
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Qianmei Fu
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Molecular Mechanisms of DUBs Regulation in Signaling and Disease. Int J Mol Sci 2021; 22:ijms22030986. [PMID: 33498168 PMCID: PMC7863924 DOI: 10.3390/ijms22030986] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
The large family of deubiquitinating enzymes (DUBs) are involved in the regulation of a plethora of processes carried out inside the cell by protein ubiquitination. Ubiquitination is a basic pathway responsible for the correct protein homeostasis in the cell, which could regulate the fate of proteins through the ubiquitin–proteasome system (UPS). In this review we will focus on recent advances on the molecular mechanisms and specificities found for some types of DUBs enzymes, highlighting illustrative examples in which the regulatory mechanism for DUBs has been understood in depth at the molecular level by structural biology. DUB proteases are responsible for cleavage and regulation of the multiple types of ubiquitin linkages that can be synthesized inside the cell, known as the ubiquitin-code, which are tightly connected to specific substrate functions. We will display some strategies carried out by members of different DUB families to provide specificity on the cleavage of particular ubiquitin linkages. Finally, we will also discuss recent progress made for the development of drug compounds targeting DUB proteases, which are usually correlated to the progress of many pathologies such as cancer and neurodegenerative diseases.
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黄 晓, 全 裕, 严 隆, 赵 琳. [Expression of ubiquitin-specific protease 7 in lung tissue of preterm rats after hyperoxia exposure]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2020; 22:1331-1337. [PMID: 33328006 PMCID: PMC7735927 DOI: 10.7499/j.issn.1008-8830.2007147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/11/2020] [Indexed: 06/12/2023]
Abstract
OBJECTIVE To study the expression and significance of ubiquitin-specific protease 7 (USP7) and the key factors of the Wnt signaling pathway in the lung tissue of preterm rats after hyperoxia exposure. METHODS A total of 180 preterm neonatal Wistar rats were randomly divided into an air control group, an air intervention group, a hyperoxia control group, and a hyperoxia intervention group, with 45 rats in each group. Lung injury was induced by hyperoxia exposure in the hyperoxia groups. The preterm rats in the intervention groups were given intraperitoneal injection of the USP7 specific inhibitor P5091 (5 mg/kg) every day. The animals were sacrificed on days 3, 5, and 9 of the experiment to collect lung tissue specimens. Hematoxylin-eosin staining was used to observe the pathological changes of lung tissue. RT-PCR and Western blot were used to measure the mRNA and protein expression levels of USP7 and the key factors of the Wnt signaling pathway β-catenin and α-smooth muscle actin (α-SMA) in lung tissue. RESULTS The air groups had normal morphology and structure of lung tissue; on days 3 and 5, the hyperoxia control group showed obvious alveolar compression and disordered structure, with obvious inflammatory cells, erythrocyte diapedesis, and interstitial edema. On day 9, the hyperoxia control group showed alveolar structural disorder and obvious thickening of the alveolar septa. Compared with the hyperoxia control group at the corresponding time points, the hyperoxia intervention group had significantly alleviated disordered structure, inflammatory cell infiltration, and bleeding in lung tissue. At each time point, the hyperoxia groups had a significantly lower radial alveolar count (RAC) than the corresponding air groups (P < 0.05), and the hyperoxia intervention group had a significantly higher RAC than the hyperoxia control group (P < 0.05). On days 3, 5, and 9 of the experiment, the hyperoxia groups had significantly higher mRNA expression of USP7 and β-catenin and protein expression of USP7, β-catenin, and α-SMA than the corresponding air groups (P < 0.05). Compared with the hyperoxia control group, the hyperoxia intervention group had significant reductions in the mRNA expression of β-catenin and the protein expression of β-catenin and α-SMA (P < 0.05), while there were no significant differences in the mRNA and protein expression of USP7 between the hyperoxia intervention and hyperoxia control groups (P > 0.05). There were no significant differences in the mRNA expression of USP7 and β-catenin and the protein expression of USP7, β-catenin, and α-SMA between the air intervention and air control groups (P > 0.05). CONCLUSIONS Hyperoxia exposure can activate the Wnt/β-catenin signaling pathway, and USP7 may participate in hyperoxic lung injury through the Wnt/β-catenin signaling pathway. The USP7 specific inhibitor P5091 may accelerate the degradation of β-catenin by enhancing its ubiquitination, reduce lung epithelial-mesenchymal transition, and thus exert a certain protective effect against hyperoxic lung injury.
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Affiliation(s)
- 晓悦 黄
- 桂林医学院附属医院新生儿科, 广西 桂林 541001Department of Neonatology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - 裕凤 全
- 桂林医学院附属医院新生儿科, 广西 桂林 541001Department of Neonatology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - 隆丽 严
- 广东省妇幼保健院新生儿科, 广东 广州 511400Department of Neonatology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - 琳 赵
- 河北省儿童医院新生儿科, 河北 石家庄 050000
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Kaushal K, Ramakrishna S. Deubiquitinating Enzyme-Mediated Signaling Networks in Cancer Stem Cells. Cancers (Basel) 2020; 12:E3253. [PMID: 33158118 PMCID: PMC7694198 DOI: 10.3390/cancers12113253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs) have both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Thus, CSCs are considered to be promising therapeutic targets for cancer therapy. The function of CSCs can be regulated by ubiquitination and deubiquitination of proteins related to the specific stemness of the cells executing various stem cell fate choices. To regulate the balance between ubiquitination and deubiquitination processes, the disassembly of ubiquitin chains from specific substrates by deubiquitinating enzymes (DUBs) is crucial. Several key developmental and signaling pathways have been shown to play essential roles in this regulation. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of CSCs. These signaling pathways have been experimentally shown to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. In this review, we focus on the DUBs involved in CSCs signaling pathways, which are vital in regulating their stem-cell fate determination.
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Affiliation(s)
- Kamini Kaushal
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea;
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea;
- College of Medicine, Hanyang University, Seoul 04763, Korea
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Yang Y, Fan X, Ren Y, Wu K, Tian X, Wen F, Liu D, Fan Y, Zhao S. SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 23:200-214. [PMID: 33376627 PMCID: PMC7750169 DOI: 10.1016/j.omtn.2020.10.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023]
Abstract
Esophageal cancer (EC) is a highly aggressive disease, and its progression involves a complex gene regulation network. Transcription factor SOX2 is amplified in various cancers including EC. A pathway involving SOX2 regulation of microRNAs (miRNAs) and their target genes has been previously revealed. This study aims to delineate the ability of SOX2 to influence the EC progression, with the involvement of miR-30e/USP4/SMAD4/CK2 axis. SOX2 expression was first examined in the clinical tissue samples from 30 EC patients. Effects of SOX2 on proliferation, migration, and invasion alongside tumorigenicity of transfected cells were examined by means of gain- and loss-of-function experiments. EC tissues and cells exhibited high expression of SOX2, miR-30e, and CK2 and poor expression of USP4 and SMAD4. Mechanistically, SOX2 was positively correlated with miR-30e and upregulated the expression of miR-30e. miR-30e specifically targeted USP4, which induced deubiquitination of SMAD4 and promoted its expression. Meanwhile, SMAD4 was enriched in the CK2 promoter region and thus inhibited its expression. SOX2 stimulated EC cell proliferative, invasive, and migratory capacities in vitro and tumor growth in vivo by regulating the miR-30e/USP4/SMAD4/CK2 axis. Collectively, our work reveals a novel SOX2-mediated regulatory network in EC that may be a viable target for EC treatment.
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Affiliation(s)
- Yang Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Xin Fan
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Yukai Ren
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Kai Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Xiangyu Tian
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Fengbiao Wen
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Donglei Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Yuxia Fan
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
- Corresponding author Yuxia Fan, Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
| | - Song Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
- Corresponding author Song Zhao, Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
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