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Han F, Qi G, Li R, Peng J, Yan S, Yuan C, Kong B, Ma H. USP28 promotes PARP inhibitor resistance by enhancing SOX9-mediated DNA damage repair in ovarian cancer. Cell Death Dis 2025; 16:305. [PMID: 40240356 PMCID: PMC12003857 DOI: 10.1038/s41419-025-07647-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage repair (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.
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Affiliation(s)
- Fang Han
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Gonghua Qi
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Jiali Peng
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Shi Yan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Cunzhong Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Hanlin Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.
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Wen W, Zhou Z, Chen C, Chen M. Deubiquitinase USP28 promotes the malignant progression and radio-resistance of hepatocellular carcinoma by stabilizing WDHD1. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03793-w. [PMID: 39928151 DOI: 10.1007/s00210-025-03793-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/06/2025] [Indexed: 02/11/2025]
Abstract
Radio-resistance is a principal culprit in radiation therapy for hepatocellular carcinoma (HCC). Insights on the regulation genes of radio-resistance and underlying mechanisms in HCC are awaiting profound investigation. This study is designed to explore the role and mechanism of WD repeat and HMG-box DNA binding protein 1 (WDHD1) in HCC progression. WDHD1 mRNA level was detected using real-time quantitative polymerase chain reaction (RT-qPCR). WDHD1, ubiquitin-specific protease 28 (USP28), E-cadherin, N-cadherin, and vimentin protein levels were determined by Western blot. Cell viability, cell cycle progression, migration, invasion, and apoptosis were assessed using the cell counting kit-8 (CCK-8) assay, flow cytometry, wound healing assay, and Transwell assay. The radio-sensitivity of HCC cells was analyzed using a colony formation assay. After UbiBrowser database analysis, the interaction between USP28 and WDHD1 was verified using GST pull-down and Co-immunoprecipitation (CoIP) assay. Xenograft assay was used to test the effect of USP28 on radio-sensitivity in vivo. WDHD1 and USP28 were highly expressed in HCC patients and cell lines. Moreover, WDHD1 knockdown could repress HCC cell proliferation, migration, invasion, epithelial to mesenchymal transition (EMT), and enhance the radiosensitivity. Mechanistically, USP28 mediated the deubiquitination and stabilization of WDHD1 through its direct interaction. USP28 silencing increased the radiosensitivity of HCC in vivo. USP28 contributed to HCC development and radio-resistance through deubiquitinating WDHD1, providing a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Wu Wen
- Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhenhua Zhou
- Department of Hepato-Biliary-Pancreatic Surgery, The Affiliated Huaihua Hospital of University of South China, Huaihua, China
| | - Chao Chen
- Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Ming Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69, Chuanshan Road, Hengyang City, 421001, Hunan Province, China.
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Wu L, Wang J, Chai L, Chen J, Jin X. Roles of deubiquitinases in urologic cancers (Review). Oncol Lett 2024; 28:609. [PMID: 39525605 PMCID: PMC11544529 DOI: 10.3892/ol.2024.14743] [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: 07/23/2024] [Accepted: 09/23/2024] [Indexed: 11/16/2024] Open
Abstract
Human health is endangered by the occurrence and progression of urological cancers, including renal cell carcinoma, prostate cancer and bladder cancer, which are usually associated with the activation of oncogenic factors and inhibition of cancer suppressors. The primary mechanism for protein breakdown in cells is the ubiquitin-proteasome system, whilst deubiquitinases contribute to the reversal of this process. However, both are important for protein homeostasis. Deubiquitination may also be involved in the control of the cell cycle, proliferation and apoptosis, and dysregulated deubiquitination is associated with the malignant transformation, invasion and metastasis of urologic malignancies. Therefore, a comprehensive summary of the mechanisms underlying deubiquitination in urological cancers may provide novel strategies and insights for diagnosis and treatment. The present review aimed to methodically clarify the role of deubiquitinating enzymes in urinary system cancers as well as their prospective application prospects for clinical treatment.
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Affiliation(s)
- Liangpei Wu
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Jiahui Wang
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Lin Chai
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Jun Chen
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
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Cotino-Nájera S, García-Villa E, Cruz-Rosales S, Gariglio P, Díaz-Chávez J. Resveratrol inhibits Lin28A expression and induces its degradation via the proteasomal pathway in NCCIT cells. Oncol Lett 2024; 28:577. [PMID: 39397804 PMCID: PMC11467847 DOI: 10.3892/ol.2024.14710] [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: 04/29/2024] [Accepted: 08/14/2024] [Indexed: 10/15/2024] Open
Abstract
Lin28A is an oncoprotein overexpressed in several cancer types such as testicular, ovarian, colon, breast and lung cancers. As a pluripotency factor that promotes tumorigenesis, Lin28A is associated with more undifferentiated and aggressive tumors phenotypes. Moreover, Lin28A is a highly stable protein that is difficult to downregulate. The compound resveratrol (RSV) has anticancer effects. The present study aimed to elucidate the mechanisms underlying the downregulation of Lin28A protein expression by RSV in the NCCIT cell line. NCCIT cells were treated with different concentrations of RSV to investigate its effects on Lin28A expression. The mRNA expression levels of Lin28A and ubiquitin-specific protease 28 (USP28) were assessed using reverse transcription-quantitative PCR. Western blot analysis was employed to evaluate the protein levels of Lin28A, USP28 and phosphorylated Lin28A. In addition, in some experiments, cells were treated with a MAPK/ERK pathway inhibitor, and other experiments involved transfecting cells with small interfering RNAs targeting USP28. The results demonstrated that RSV significantly reduced Lin28A expression by destabilizing the protein; this effect was mediated by the ability of RSV to suppress the expression of USP28, a deubiquitinase that normally protects Lin28A from ubiquitination and degradation. Additionally, RSV inhibited phosphorylation of Lin28A via the MAPK/ERK pathway; this phosphorylation event has previously been shown to enhance the stability of Lin28A by increasing its half-life. This resulted in Lin28A degradation through the proteasomal pathway in NCCIT cells. The results provide further evidence of the anticancer activity of RSV, and identified Lin28A and USP28 as promising therapeutic targets. As a stable oncoprotein, downregulating Lin28A expression is challenging. However, the present study demonstrated that RSV can overcome this hurdle by inhibiting USP28 expression and MAPK/ERK signaling to promote Lin28A degradation. Furthermore, elucidating these mechanisms provides avenues for developing targeted cancer therapies.
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Affiliation(s)
- Sandra Cotino-Nájera
- Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - Enrique García-Villa
- Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - Samantha Cruz-Rosales
- Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - Patricio Gariglio
- Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - José Díaz-Chávez
- Biomedical Cancer Research Unit, Biomedical Research Institute, National Autonomous University of Mexico/National Cancer Institute, Mexico City 14080, Mexico
- Department of Cellular Biology, Faculty of Sciences, National Autonomous University of Mexico, Mexico City 04510, Mexico
- School of Medicine and Health Sciences, Monterrey Institute of Technology, Mexico City 14380, Mexico
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5
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Sun K, Zhi Y, Ren W, Li S, Zheng J, Gao L, Zhi K. Crosstalk between O-GlcNAcylation and ubiquitination: a novel strategy for overcoming cancer therapeutic resistance. Exp Hematol Oncol 2024; 13:107. [PMID: 39487556 PMCID: PMC11529444 DOI: 10.1186/s40164-024-00569-5] [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: 07/01/2024] [Accepted: 10/04/2024] [Indexed: 11/04/2024] Open
Abstract
Developing resistance to cancer treatments is a major challenge, often leading to disease recurrence and metastasis. Understanding the underlying mechanisms of therapeutic resistance is critical for developing effective strategies. O-GlcNAcylation, a post-translational modification that adds GlcNAc from the donor UDP-GlcNAc to serine and threonine residues of proteins, plays a crucial role in regulating protein function and cellular signaling, which are frequently dysregulated in cancer. Similarly, ubiquitination, which involves the attachment of ubiquitin to to proteins, is crucial for protein degradation, cell cycle control, and DNA repair. The interplay between O-GlcNAcylation and ubiquitination is associated with cancer progression and resistance to treatment. This review discusses recent discoveries regarding the roles of O-GlcNAcylation and ubiquitination in cancer resistance, their interactions, and potential mechanisms. It also explores how targeting these pathways may provide new opportunities to overcome cancer treatment resistance in cancer, offering fresh insights and directions for research and therapeutic development.
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Affiliation(s)
- Kai Sun
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China
- School of Stomatology, Qingdao University, Qingdao, 266003, China
| | - Yuan Zhi
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China
| | - Wenhao Ren
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China
- School of Stomatology, Qingdao University, Qingdao, 266003, China
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China
| | - Shaoming Li
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China
- School of Stomatology, Qingdao University, Qingdao, 266003, China
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China
| | - Jingjing Zheng
- School of Stomatology, Qingdao University, Qingdao, 266003, China
- Department of Endodontics, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Ling Gao
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China.
- School of Stomatology, Qingdao University, Qingdao, 266003, China.
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China.
| | - Keqian Zhi
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China.
- School of Stomatology, Qingdao University, Qingdao, 266003, China.
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao, 266003, Shandong, China.
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Han J, Lin L, Fang Z, Ye B, Han X, Xu J, Han B, Min J, Qian J, Wu G, Wang Y, Liang G. Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21. Theranostics 2024; 14:6236-6248. [PMID: 39431010 PMCID: PMC11488095 DOI: 10.7150/thno.99340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 09/21/2024] [Indexed: 10/22/2024] Open
Abstract
Rationale: Cardiac hypertrophy is an important pathological basis for heart failure. Most physiological activities of cardiomyocytes are regulated by proteins and their post-translational modification. Deubiquitinating enzymes (DUBs) are involved in protein stability maintenance and closely related to myocardial hypertrophy. In this study, we aimed to clarify the regulatory role of a DUB, ubiquitin-specific peptidase 28 (USP28), in cardiac hypertrophy and explore the molecular mechanism behind. Methods: Transcriptome and single-cell mRNA sequencing was used to demonstrate the association of USP28 and cardiac hypertrophy. Cardiomyocyte-specific USP28 knockout mice (USP28CKO) were subjected to angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) models. Coimmunoprecipitation combined mass spectrum analysis (Co-IP/MS) was applied to screen out the substrate of USP28. Results: We first showed the up-regulation of USP28 in cardiac hypertrophy, and its cellular localization of cardiomyocytes. USP28CKO protects mouse heart against Ang II- or TAC-induced cardiac dysfunction and hypertrophy. Mechanistically, we identified tripartite motif-containing protein 21 (TRIM21) as the potential substrate of USP28 by Co-IP/MS analysis. Cardiomyocyte USP28 deubiquitinates and stabilizes TRIM21 to negatively regulate nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response, increasing oxidative stress in cardiomyocytes and promoting cardiac hypertrophy and injury. Finally, using a selective USP28 inhibitor Otilonium Bromide, we confirmed the therapeutic effect of pharmacological inhibition of USP28 against TAC-induced established hypertrophic heart failure. Conclusion: Our study illustrates a cardiomyocyte-specific USP28-TRIM21 axis in regulating hypertrophic cardiomyopathy and presents USP28 as a potential target for the treatment of cardiac hypertrophy.
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Affiliation(s)
- Jibo Han
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Cardiology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Liming Lin
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zimin Fang
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bozhi Ye
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xue Han
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Pharmacy and School of Pharmaceutical Sciences, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jiachen Xu
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Binjiang Han
- Department of Cardiology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Julian Min
- Department of Pharmacy and School of Pharmaceutical Sciences, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jinfu Qian
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gaojun Wu
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Pharmaceutical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Guang Liang
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Pharmacy and School of Pharmaceutical Sciences, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
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Le Menn G, Pikkarainen K, Mennerich D, Miroszewska D, Kietzmann T, Chen Z. USP28 protects development of inflammation in mouse intestine by regulating STAT5 phosphorylation and IL22 production in T lymphocytes. Front Immunol 2024; 15:1401949. [PMID: 39076972 PMCID: PMC11284026 DOI: 10.3389/fimmu.2024.1401949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 06/27/2024] [Indexed: 07/31/2024] Open
Abstract
Introduction Ubiquitin-specific proteases (USPs), a large subset of more than 50 deubiquitinase proteins, have recently emerged as promising targets in cancer. However, their role in immune cell regulation, particularly in T cell activation, differentiation, and effector functions, remains largely unexplored. Methods We utilized a USP28 knockout mouse line to study the effect of USP28 on T cell activation and function, and its role in intestinal inflammation using the dextran sulfate sodium (DSS)-induced colitis model and a series of in vitro assays. Results Our results show that USP28 exerts protective effects in acute intestinal inflammation. Mechanistically, USP28 knockout mice (USP28-/-) exhibited an increase in total T cells mainly due to an increased CD8+ T cell content. Additionally, USP28 deficiency resulted in early defects in T cell activation and functional changes. Specifically, we observed a reduced expression of IL17 and an increase in inducible regulatory T (iTreg) suppressive functions. Importantly, activated T cells lacking USP28 showed increased STAT5 phosphorylation. Consistent with these findings, these mice exhibited increased susceptibility to acute DSS-induced intestinal inflammation, accompanied by elevated IL22 cytokine levels. Conclusions Our findings demonstrate that USP28 is essential for T cell functionality and protects mice from acute DSS-induced colitis by regulating STAT5 signaling and IL22 production. As a T cell regulator, USP28 plays a crucial role in immune responses and intestinal health.
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Affiliation(s)
- Gwenaëlle Le Menn
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Keela Pikkarainen
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Daniela Mennerich
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Dominika Miroszewska
- Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, University of Gdańsk, Gdańsk, Poland
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Zhi Chen
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
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Di Gregorio J, Di Giuseppe L, Terreri S, Rossi M, Battafarano G, Pagliarosi O, Flati V, Del Fattore A. Protein Stability Regulation in Osteosarcoma: The Ubiquitin-like Modifications and Glycosylation as Mediators of Tumor Growth and as Targets for Therapy. Cells 2024; 13:537. [PMID: 38534381 PMCID: PMC10969184 DOI: 10.3390/cells13060537] [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: 02/14/2024] [Revised: 03/11/2024] [Accepted: 03/16/2024] [Indexed: 03/28/2024] Open
Abstract
The identification of new therapeutic targets and the development of innovative therapeutic approaches are the most important challenges for osteosarcoma treatment. In fact, despite being relatively rare, recurrence and metastatic potential, particularly to the lungs, make osteosarcoma a deadly form of cancer. In fact, although current treatments, including surgery and chemotherapy, have improved survival rates, the disease's recurrence and metastasis are still unresolved complications. Insights for analyzing the still unclear molecular mechanisms of osteosarcoma development, and for finding new therapeutic targets, may arise from the study of post-translational protein modifications. Indeed, they can influence and alter protein structure, stability and function, and cellular interactions. Among all the post-translational modifications, ubiquitin-like modifications (ubiquitination, deubiquitination, SUMOylation, and NEDDylation), as well as glycosylation, are the most important for regulating protein stability, which is frequently altered in cancers including osteosarcoma. This review summarizes the relevance of ubiquitin-like modifications and glycosylation in osteosarcoma progression, providing an overview of protein stability regulation, as well as highlighting the molecular mediators of these processes in the context of osteosarcoma and their possible targeting for much-needed novel therapy.
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Affiliation(s)
- Jacopo Di Gregorio
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Laura Di Giuseppe
- Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University, 00185 Rome, Italy;
| | - Sara Terreri
- Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.T.); (M.R.); (G.B.); (O.P.); (A.D.F.)
| | - Michela Rossi
- Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.T.); (M.R.); (G.B.); (O.P.); (A.D.F.)
| | - Giulia Battafarano
- Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.T.); (M.R.); (G.B.); (O.P.); (A.D.F.)
| | - Olivia Pagliarosi
- Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.T.); (M.R.); (G.B.); (O.P.); (A.D.F.)
| | - Vincenzo Flati
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Andrea Del Fattore
- Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.T.); (M.R.); (G.B.); (O.P.); (A.D.F.)
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9
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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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Barchielli G, Capperucci A, Tanini D. Therapeutic cysteine protease inhibitors: a patent review (2018-present). Expert Opin Ther Pat 2024; 34:17-49. [PMID: 38445468 DOI: 10.1080/13543776.2024.2327299] [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: 10/09/2023] [Accepted: 03/04/2024] [Indexed: 03/07/2024]
Abstract
INTRODUCTION Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role in the onset and progression of several diseases, including cancer, immune-related and neurodegenerative disease, viral and parasitic infections, cysteine proteases represent an attractive drug target for the development of therapeutic tools. AREAS COVERED Recent scientific and patent literature focusing on the design and study of cysteine protease inhibitors with potential therapeutic application has been reviewed. EXPERT OPINION The discovery of a number of effective structurally diverse cysteine protease inhibitors opened up new challenges and opportunities for the development of therapeutic tools. Mechanistic studies and the availability of X-ray crystal structures of some proteases, alone and in complex with inhibitors, provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors as preclinical candidates for the treatment of different diseases.
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Affiliation(s)
- Giulia Barchielli
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino FI, Italy
| | - Antonella Capperucci
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino FI, Italy
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11
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Abstract
Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and, eventually, metastasis. The attachment of ubiquitin signals by E3 ubiquitin ligases is directly opposed by the action of approximately 100 deubiquitinating enzymes (DUBs) in humans. Together, DUBs and E3 ligases coordinate ubiquitin signalling by providing selectivity for different substrates and/or ubiquitin signals. The balance between ubiquitination and deubiquitination is exquisitely controlled to ensure properly coordinated proteostasis and response to cellular stimuli and stressors. Not surprisingly, then, DUBs have been associated with all hallmarks of cancer. These relationships are often complex and multifaceted, highlighted by the implication of multiple DUBs in certain hallmarks and by the impact of individual DUBs on multiple cancer-associated pathways, sometimes with contrasting cancer-promoting and cancer-inhibiting activities, depending on context and tumour type. Although it is still understudied, the ever-growing knowledge of DUB function in cancer physiology will eventually identify DUBs that warrant specific inhibition or activation, both of which are now feasible. An integrated appreciation of the physiological consequences of DUB modulation in relevant cancer models will eventually lead to the identification of patient populations that will most likely benefit from DUB-targeted therapies.
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Affiliation(s)
- Grant Dewson
- Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
| | - Pieter J A Eichhorn
- Curtin Medical School, Curtin University, Perth, Western Australia, Australia.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
| | - David Komander
- Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
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12
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Varela K, Arman HD, Berger MS, Sponsel VM, Lin CHA, Yoshimoto FK. Inhibition of Cysteine Proteases via Thiol-Michael Addition Explains the Anti-SARS-CoV-2 and Bioactive Properties of Arteannuin B. JOURNAL OF NATURAL PRODUCTS 2023; 86:1654-1666. [PMID: 37458412 DOI: 10.1021/acs.jnatprod.2c01146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SARS-CoV-2. In this study, a methyl ester derivative of arteannuin B was isolated when A. annua leaves were extracted with a 1:1 mixture of methanol and dichloromethane. This methyl ester was thought to be formed from the reaction between arteannuin B and the extracting solvent, which was supported by the fact that arteannuin B underwent 1,2-addition when it was dissolved in deuteromethanol. In contrast, in the presence of N-acetylcysteine methyl ester, a 1,4-addition (thiol-Michael reaction) occurred. Arteannuin B hindered the activity of the SARS CoV-2 main protease (nonstructural protein 5, NSP5), a cysteine protease, through time-dependent inhibition. The active site cysteine residue of NSP5 (cysteine-145) formed a covalent bond with arteannuin B as determined by mass spectrometry. In order to determine whether cysteine adduction by arteannuin B can inhibit the development of cancer cells, similar experiments were performed with caspase-8, the cysteine protease enzyme overexpressed in glioblastoma. Time-dependent inhibition and cysteine adduction assays suggested arteannuin B inhibits caspase-8 and adducts to the active site cysteine residue (cysteine-360), respectively. Overall, these results enhance our understanding of how A. annua possesses antiviral and cytotoxic activities.
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Affiliation(s)
- Kaitlyn Varela
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States
| | - Hadi D Arman
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States
| | - Mitchel S Berger
- Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94122, United States
| | - Valerie M Sponsel
- Department of Integrative Biology, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States
| | - Chin-Hsing Annie Lin
- Department of Integrative Biology, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States
| | - Francis K Yoshimoto
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, Texas 78249, United States
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