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Wang T, Bai Y, Dong Y, Qin J, Zhou X, Wang A, Liu D, Li X, Ma Z, Hu Y. A comprehensive analysis of deubiquitinase USP20 on prognosis and immunity in pan-cancer. FASEB J 2025; 39:e70499. [PMID: 40270318 DOI: 10.1096/fj.202402603r] [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: 10/27/2024] [Revised: 02/05/2025] [Accepted: 03/20/2025] [Indexed: 04/25/2025]
Abstract
USP20 is a deubiquitinase enzyme in the ubiquitin-proteasome system that plays a role in the development and progression of tumors. However, the relationships between USP20 expression and clinical prognosis and tumor immunity remain unclear. In this study, the USP20 expression and its relationships with potential prognostic value, the tumor microenvironment (TME), immune-related genes, the tumor mutational burden (TMB), microsatellite instability (MSI), homologous recombination deficiency, cancer stemness, and correlated signaling pathways were investigated via The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), STRING, Gene Expression Profiling Interactive Analysis (GEPIA2), and the Human Protein Atlas (HPA). Moreover, we explored the oncogenic capability of USP20 in breast cancer. Data analysis was performed via GraphPad Prism and the R package. The results indicated that the expression of USP20 was upregulated in most cancers and was associated with survival in 17 tumor types. Furthermore, USP20 expression was strongly correlated with immune infiltration and the expression of immunomodulatory genes. We also verified the correlations between USP20 expression and tumor heterogeneity, cancer stemness, and the corresponding signaling pathways. Moreover, our work revealed that USP20 was highly expressed and predicted a poor outcome in patients with breast cancer. Basic experiments verified that USP20 overexpression promoted both the proliferation and migration of breast cancer cells. This study comprehensively investigated the expression of USP20 and its correlation with clinical prognostic assessment and tumor immune modulation across cancers, indicating that USP20 might have utility as a biomarker associated with prognosis and cancer immunotherapy.
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Affiliation(s)
- Ting Wang
- School of Medicine, Nankai University, Tianjin, China
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
| | - Yibing Bai
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
- Graduate School, Medical School of Chinese PLA, Beijing, China
| | - Yi Dong
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
- Graduate School, Medical School of Chinese PLA, Beijing, China
| | - Jiapei Qin
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
- Graduate School, Medical School of Chinese PLA, Beijing, China
| | - Xin Zhou
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
- Graduate School, Medical School of Chinese PLA, Beijing, China
| | - An Wang
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
- Graduate School, Medical School of Chinese PLA, Beijing, China
| | - Dong Liu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xiaoyan Li
- Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhiqiang Ma
- Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yi Hu
- School of Medicine, Nankai University, Tianjin, China
- Department of Oncology, The First Medical Center of PLA General Hospital, Beijing, China
- Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
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Santelices J, Schultz A, Walker A, Adams N, Tirado D, Barker H, Eshraghi A, Czyż DM, Ferraro MJ. Targeting deubiquitinating enzymes (DUBs) and ubiquitin pathway modulators to enhance host defense against bacterial infections. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.27.635188. [PMID: 39975367 PMCID: PMC11838268 DOI: 10.1101/2025.01.27.635188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic approaches. This study explores host-targeted therapies (HTTs) by focusing on deubiquitinating enzymes (DUBs), essential modulators of the ubiquitin-proteasome system (UPS) that regulate host-pathogen interactions during many bacterial infections. Using Salmonella-infected macrophages as a model, we identified UPS modulators that enhance bacterial clearance and observed significant changes in DUB expression, particularly USP25, USP46, and Otud7b. The small-molecule DUB inhibitor AZ-1 significantly reduced intracellular bacterial loads in vitro and mitigated early disease severity in a murine model by decreasing fecal bacterial loads and preserving host weight. However, AZ-1 alone did not achieve complete clearance of Salmonella and required combination with extracellular-targeting antibiotics for optimal efficacy. Notably, AZ-1 demonstrated broad-spectrum activity against multidrug-resistant pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Transcriptomic analyses revealed infection-induced DUB regulation and highlighted pathways modulating immune responses, including TNF-α secretion. These findings highlight the potential of targeting the UPS as a host-directed antimicrobial strategy and provide a foundation for developing innovative therapies to combat antimicrobial resistance.
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Affiliation(s)
- John Santelices
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Alexander Schultz
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Alyssa Walker
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Nicole Adams
- Department of Infectious Diseases & Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Deyaneira Tirado
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Hailey Barker
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Aria Eshraghi
- Department of Infectious Diseases & Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Daniel M. Czyż
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Mariola J. Ferraro
- Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA
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Al-Eidan A, Draper B, Wang S, Coke B, Skipp P, Wang Y, Ewing RM. Knockdown Proteomics Reveals USP7 as a Regulator of Cell-Cell Adhesion in Colorectal Cancer via AJUBA. Mol Cell Proteomics 2024; 23:100878. [PMID: 39522755 PMCID: PMC11697772 DOI: 10.1016/j.mcpro.2024.100878] [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: 02/23/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
Ubiquitin-specific protease 7 (USP7) is implicated in many cancers including colorectal cancer in which it regulates cellular pathways such as Wnt signaling and the P53-MDM2 pathway. With the discovery of small-molecule inhibitors, USP7 has also become a promising target for cancer therapy and therefore systematically identifying USP7 deubiquitinase interaction partners and substrates has become an important goal. In this study, we selected a colorectal cancer cell model that is highly dependent on USP7 and in which USP7 knockdown significantly inhibited colorectal cancer cell viability, colony formation, and cell-cell adhesion. We then used inducible knockdown of USP7 followed by LC-MS/MS to quantify USP7-dependent proteins. We identified the Ajuba LIM domain protein as an interacting partner of USP7 through co-IP, its substantially reduced protein levels in response to USP7 knockdown, and its sensitivity to the specific USP7 inhibitor FT671. The Ajuba protein has been shown to have oncogenic functions in colorectal and other tumors, including regulation of cell-cell adhesion. We show that both knockdown of USP7 or Ajuba results in a substantial reduction of cell-cell adhesion, with concomitant effects on other proteins associated with adherens junctions. Our findings underlie the role of USP7 in colorectal cancer through its protein interaction networks and show that the Ajuba protein is a component of USP7 protein networks present in colorectal cancer.
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Affiliation(s)
- Ahood Al-Eidan
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom; Department of Biology, College of Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Ben Draper
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Siyuan Wang
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Brandon Coke
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Paul Skipp
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Yihua Wang
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Rob M Ewing
- School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.
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Tak J, Nguyen TK, Lee K, Kim SG, Ahn HC. Utilizing machine learning to identify nifuroxazide as an inhibitor of ubiquitin-specific protease 21 in a drug repositioning strategy. Biomed Pharmacother 2024; 174:116459. [PMID: 38518599 DOI: 10.1016/j.biopha.2024.116459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/29/2024] [Accepted: 03/15/2024] [Indexed: 03/24/2024] Open
Abstract
Ubiquitin-specific protease (USP), an enzyme catalyzing protein deubiquitination, is involved in biological processes related to metabolic disorders and cancer proliferation. We focused on constructing predictive models tailored to unveil compounds boasting USP21 inhibitory attributes. Six models, Extra Trees Classifier, Random Forest Classifier, LightGBM Classifier, XGBoost Classifier, Bagging Classifier, and a convolutional neural network harnessed from empirical data were selected for the screening process. These models guided our selection of 26 compounds from the FDA-approved drug library for further evaluation. Notably, nifuroxazide emerged as the most potent inhibitor, with a half-maximal inhibitory concentration of 14.9 ± 1.63 μM. The stability of protein-ligand complexes was confirmed using molecular modeling. Furthermore, nifuroxazide treatment of HepG2 cells not only inhibited USP21 and its established substrate ACLY but also elevated p-AMPKα, a downstream functional target of USP21. Intriguingly, we unveiled the previously unknown capacity of nifuroxazide to increase the levels of miR-4458, which was identified as downregulating USP21. This discovery was substantiated by manipulating miR-4458 levels in HepG2 cells, resulting in corresponding changes in USP21 protein levels in line with its predicted interaction with ACLY. Lastly, we confirmed the in vivo efficacy of nifuroxazide in inhibiting USP21 in mice livers, observing concurrent alterations in ACLY and p-AMPKα levels. Collectively, our study establishes nifuroxazide as a promising USP21 inhibitor with potential implications for addressing metabolic disorders and cancer proliferation. This multidimensional investigation sheds light on the intricate regulatory mechanisms involving USP21 and its downstream effects, paving the way for further exploration and therapeutic development.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Tan Khanh Nguyen
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Kyeong Lee
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea.
| | - Hee-Chul Ahn
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea.
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Zheng LL, Wang LT, Pang YW, Sun LP, Shi L. Recent advances in the development of deubiquitinases inhibitors as antitumor agents. Eur J Med Chem 2024; 266:116161. [PMID: 38262120 DOI: 10.1016/j.ejmech.2024.116161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/25/2024]
Abstract
Ubiquitination is a type of post-translational modification that covalently links ubiquitin to a target protein, which plays a critical role in modulating protein activity, stability, and localization. In contrast, this process is reversed by deubiquitinases (DUBs), which remove ubiquitin from ubiquitinated substrates. Dysregulation of DUBs is associated with several human diseases, such as cancer, inflammation, neurodegenerative disorders, and autoimmune diseases. Thus, DUBs have become promising targets for drug development. Although the physiological and pathological effects of DUBs are increasingly well understood, the clinical drug discovery of selective DUB inhibitors has been challenging. Herein, we summarize the structures and functions of main classes of DUBs and discuss the recent progress in developing selective small-molecule DUB inhibitors as antitumor agents.
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Affiliation(s)
- Li-Li Zheng
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li-Ting Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Ye-Wei Pang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
| | - Lei Shi
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
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Tang G, Huang S, Luo J, Wu Y, Zheng S, Tong R, Zhong L, Shi J. Advances in research on potential inhibitors of multiple myeloma. Eur J Med Chem 2023; 262:115875. [PMID: 37879169 DOI: 10.1016/j.ejmech.2023.115875] [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: 08/31/2023] [Revised: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 10/27/2023]
Abstract
Multiple myeloma (MM) is a common hematological malignancy. Although recent clinical applications of immunomodulatory drugs, proteasome inhibitors and CD38-targeting antibodies have significantly improved the outcome of MM patient with increased survival, the incidence of drug resistance and severe treatment-related complications is gradually on the rise. This review article summarizes the characteristics and clinical investigations of several MM drugs in clinical trials, including their structures, mechanisms of action, structure-activity relationships, and clinical study progress. Furthermore, the application potentials of the drugs that have not yet entered clinical trials are also reviewed. The review also outlines the future directions of MM drug development.
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Affiliation(s)
- Guoyuan Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shan Huang
- Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Ji Luo
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Yingmiao Wu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Shuai Zheng
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Rongsheng Tong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
| | - Ling Zhong
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan, 610044, China.
| | - Jianyou Shi
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
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Autophagy/Mitophagy Regulated by Ubiquitination: A Promising Pathway in Cancer Therapeutics. Cancers (Basel) 2023; 15:cancers15041112. [PMID: 36831455 PMCID: PMC9954143 DOI: 10.3390/cancers15041112] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Autophagy is essential for organismal development, maintenance of energy homeostasis, and quality control of organelles and proteins. As a selective form of autophagy, mitophagy is necessary for effectively eliminating dysfunctional mitochondria. Both autophagy and mitophagy are linked with tumor progression and inhibition. The regulation of mitophagy and autophagy depend upon tumor type and stage. In tumors, mitophagy has dual roles: it removes damaged mitochondria to maintain healthy mitochondria and energy production, which are necessary for tumor growth. In contrast, mitophagy has been shown to inhibit tumor growth by mitigating excessive ROS production, thus preventing mutation and chromosomal instability. Ubiquitination and deubiquitination are important modifications that regulate autophagy. Multiple E3 ubiquitin ligases and DUBs modulate the activity of the autophagy and mitophagy machinery, thereby influencing cancer progression. In this review, we summarize the mechanistic association between cancer development and autophagy/mitophagy activities regulated by the ubiquitin modification of autophagic proteins. In addition, we discuss the function of multiple proteins involved in autophagy/mitophagy in tumors that may represent potential therapeutic targets.
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Qin B, Zhou L, Wang F, Wang Y. Ubiquitin-specific protease 20 in human disease: emerging role and therapeutic implications. Biochem Pharmacol 2022; 206:115352. [DOI: 10.1016/j.bcp.2022.115352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/06/2022] [Accepted: 11/15/2022] [Indexed: 11/23/2022]
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The emerging role of ubiquitin-specific protease 20 in tumorigenesis and cancer therapeutics. Cell Death Dis 2022; 13:434. [PMID: 35508480 PMCID: PMC9068925 DOI: 10.1038/s41419-022-04853-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 04/02/2022] [Accepted: 04/12/2022] [Indexed: 12/13/2022]
Abstract
As a critical member of the ubiquitin-specific proteolytic enzyme family, ubiquitin-specific peptidase 20 (USP20) regulates the stability of proteins via multiple signaling pathways. In addition, USP20 upregulation is associated with various cellular biological processes, such as cell cycle progression, proliferation, migration, and invasion. Emerging studies have revealed the pivotal role of USP20 in the tumorigenesis of various cancer types, such as breast cancer, colon cancer, lung cancer, gastric cancer and adult T cell leukemia. In our review, we highlight the different mechanisms of USP20 in various tumor types and demonstrate that USP20 regulates the stability of multiple proteins. Therefore, regulating the activity of USP20 is a novel tumor treatment. However, the clinical significance of USP20 in cancer treatment merits more evidence. Finally, different prospects exist for the continued research focus of USP20.
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Guan Y, Jiang SR, Liu JG, Shi JR, Liu ZB. USP20 regulates the stability of EMT transcription factor SOX4 and influences colorectal cancer metastasis. Pathol Res Pract 2022; 233:153879. [PMID: 35405623 DOI: 10.1016/j.prp.2022.153879] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/28/2021] [Accepted: 04/01/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is a familiar malignancy accompanied by higher morbidity and mortality. The deubiquitination enzyme USP20 has been discovered to be one key factor in several cancers progression. SOX4 is a critical transcription factor to regulate the expression of various genes, and participates into the occurrence and progression of cancers. In this study, it was aimed to illustrate the role of USP20 and the regulatory relationship between USP20 and SOX4 in CRC. METHODS The protein expressions of USP20, SOX4, E-cadherin, N-cadherin, Snail and slug were tested through western blot. The cell proliferation ability was verified through CCK-8 assay. The migration and invasion abilities were detected through Transwell assay. The mRNA expression of SOX4 was confirmed through RT-qPCR. The interaction between USP20 and SOX4 was notarized through Co-IP assay. RESULT Our study demonstrated that USP20 displayed higher expression, and facilitated CRC progression through regulating cell proliferation, migration, invasion and EMT process markers. USP20 was found to modulate SOX4 protein expression. Next, it was verified that USP20 regulated SOX4 degradation through deubiquitination. Finally, through rescue assays, we revealed that USP20 mediated SOX4 expression to accelerate CRC progression. CONCLUSIONS In this study, USP20 regulated the stability of EMT transcription factor SOX4 and aggravated colorectal cancer metastasis. This finding might highlight the function of USP20 in the treatment of CRC.
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Affiliation(s)
- Yu Guan
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Shi-Ru Jiang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Jun-Guang Liu
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Ji-Rong Shi
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Zhan-Bing Liu
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China.
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Cheng CP, Liu ST, Chiu YL, Huang SM, Ho CL. The Inhibitory Effects of 6-Thioguanine and 6-Mercaptopurine on the USP2a Target Fatty Acid Synthase in Human Submaxillary Carcinoma Cells. Front Oncol 2021; 11:749661. [PMID: 34956872 PMCID: PMC8702617 DOI: 10.3389/fonc.2021.749661] [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: 09/13/2021] [Accepted: 11/22/2021] [Indexed: 11/15/2022] Open
Abstract
Overexpression of the deubiquitinase USP2a leads to stabilization of fatty acid synthase (FAS), the levels of which are often elevated in aggressive human cancers. Consequently, there is an urgent need for inhibitors to suppress the deubiquitination activity of USP2a so as to upregulate FAS protein degradation. We first analyzed the relationship between the expression level of USP2a and survival using The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (HNSC) data collection. Our results suggested survival rates were lower among HNSC patients expressing higher levels of USP2a. We then investigated two thiopurine drugs, 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP), to determine whether they could potentially serve as inhibitors of USP2a. Western blot analysis showed that levels of two USP2a target proteins, FAS and Mdm2, were dose-dependently decreased in A253 submaxillary carcinoma cells treated with 6-TG or 6‐MP. Responding to the degradation of Mdm2, levels of p53 were increased. We found that 6-TG and 6-MP also suppressed levels of both USP2a mRNA and protein, suggesting these two thiopurines do not act solely through direct inhibition of USP2a. The effects of 6-TG and 6-MP were not cell type-specific, as they elicited similar decreases in FAS protein in leukemia, prostate and cervical cancer cell lines. 6-TG and 6-MP had effects on several cell cycle proteins, including another USP2a target protein, cyclin D1. The populations of cells in subG1 and S phase were increased by 6-TG and 6-MP, which was accompanied by reductions in G1 phase cells. In untreated cells, USP2a transfection increased FAS and cyclin D1 levels compared to an enzyme-dead USP2a C276A mutant, which lacked deubiquitinating activity. However, USP2a transfection failed to reverse the suppressive effects of 6‐TG and 6-MP on FAS levels. In summary, these findings suggest 6-TG and 6-MP reduce the stability of some USP2a targets, including FAS and Mdm2, by inhibiting USP2a-catalyzed deubiquitination in some cancer cells. Our work also provides repurposing evidence supporting 6‐TG and 6-MP as target therapeutic drugs, such as USP2a/FAS in this study.
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Affiliation(s)
- Chiao-Pei Cheng
- Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Shu-Ting Liu
- Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan
| | - Yi-Lin Chiu
- Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan
| | - Shih-Ming Huang
- Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan
| | - Ching-Liang Ho
- Division of Hematology and Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
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Jia X, Chen H, Ren Y, Dejizhuoga, Gesangyuzhen, Gao N, Feng H, Huang W, Liao Y, Yu H. BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression. Exp Cell Res 2021; 402:112506. [PMID: 33516665 DOI: 10.1016/j.yexcr.2021.112506] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 01/07/2023]
Abstract
Accumulating evidence revealed the abnormal expression of KLF5 in human cancers while its role in melanoma remains uncharacterized. This study aimed to explore the role of KLF5 in the proliferation and metastasis of melanoma. Bioinformatics analysis was performed to detect WWP1, BAP1 and KLF5 expression in melanoma, followed by expression determination on clinical tissues from melanoma patients and cancer cells. The cancer cells were infected with lentivirus expressing KLF5 or BAP1 while PI3K, AKT and mTOR expression was detected and autophagy was observed. Treated cells were injected to mice when tumor growth was measured and autophagy-related protein was detected. Plasmids expressing WWP1 and Ub-K48 were co-transfected into treated melanoma cells while immunoprecipitation assay was performed to determine the interaction among KLF5, WWP1, and BAP1. WWP1 was poorly expressed in melanoma cells and tissues whereas KLF5 was highly expressed and was positively correlated to poor prognosis. KLF5 promoted melanoma cell malignant phenotypes as well as inhibited autophagy. Interestingly, KLF5 contributed to activation of PI3K-AKT-mTOR signaling pathway, thereby inhibiting autophagy in melanoma cells. WWP1 mediated K48-linked ubiquitination of KLF5 to promote its degradation, and BAP1 antagonized this modification and stabilized KLF5 protein expression. Besides, BAP1 promoted KLF5-mediated growth of melanoma in vivo. Taken altogether, BAP1 antagonized WWP1-mediated ubiquitination of KLF5 to inhibit autophagy and promote melanoma development.
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Affiliation(s)
- Xiaomin Jia
- Department of Pathology, Lhasa People's Hospital, Tibet Autonomous Region, Lhasa, 850000, PR China
| | - Hongwei Chen
- Department of General Surgery, Hunan Province Brain Hospital, Changsha, 410007, PR China
| | - Yi Ren
- Beijing Jishuitan Hospital, Beijing, 100035, PR China
| | - Dejizhuoga
- Department of Pathology, Lhasa People's Hospital, Tibet Autonomous Region, Lhasa, 850000, PR China
| | - Gesangyuzhen
- Department of Pathology, Lhasa People's Hospital, Tibet Autonomous Region, Lhasa, 850000, PR China
| | - Nina Gao
- Department of Pathology, Hunan Cancer Hospital, Changsha, 410013, PR China
| | - Hao Feng
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, PR China.
| | - Wei Huang
- Department of Gynaecology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, PR China.
| | - Yangying Liao
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, PR China
| | - Hong Yu
- Department of Pathology, The Third People's Hospital of Shenzhen, Shenzhen, 518000, PR China
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13
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Rong Z, Zhu Z, Cai S, Zhang B. Knockdown of USP8 Inhibits the Growth of Lung Cancer Cells. Cancer Manag Res 2020; 12:12415-12422. [PMID: 33293867 PMCID: PMC7719325 DOI: 10.2147/ijn.s259191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 10/15/2020] [Indexed: 01/17/2023] Open
Abstract
Purpose Lung cancer is the deadliest tumor in the world. This study aimed to investigate the effection of USP8 on the proliferation and growth of NSCLC cells. Methods The proliferation, migration, invasion, cell cycle progression, and apoptosis of A549 and H1299 cells were evaluated with CCK8, colony formation, scratch, transwell, and flow cytometry experiments. Furthermore, the expression of cell cycle- and apoptosis-related proteins was detected by western blot. Results Knockdown of USP8 inhibited the proliferation, migration, invasion, and cell cycle progression of A549 and H1299 cells, and promoted the apoptosis. The results of western blot indicated that knockdown of USP8 down-regulated the expression of Cyclin D1, CDK4, CDK6, p-AKT, and Bcl2, and up-regulated the expression of Bax. Conclusion Knockdown of USP8 inhibited the proliferation of human lung cancer cells by regulating cell cycle- and apoptosis-related proteins. USP8 may be a therapeutic target for lung cancer.
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Affiliation(s)
- Zhenhua Rong
- Minimally Invasive Surgery Oncology, The People's Hospital of Caoxian, Heze, Shandong, People's Republic of China
| | - Zongmin Zhu
- Department of Pharmacology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, People's Republic of China
| | - Shihua Cai
- Department of Outpatient, Heze Municipal Hospital, Heze 274000, Shandong, People's Republic of China
| | - Bingqing Zhang
- Department of Respiratory Medicine, Heze Municipal Hospital, Heze 274000, Shandong, People's Republic of China
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14
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Rong Z, Zhu Z, Cai S, Zhang B. Knockdown of USP8 Inhibits the Growth of Lung Cancer Cells . Cancer Manag Res 2020. [DOI: 10.2147/cmar.s259191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
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15
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Kanan D, Kanan T, Dogan B, Orhan MD, Avsar T, Durdagi S. An Integrated in silico Approach and in vitro Study for the Discovery of Small-Molecule USP7 Inhibitors as Potential Cancer Therapies. ChemMedChem 2020; 16:555-567. [PMID: 33063944 DOI: 10.1002/cmdc.202000675] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/06/2020] [Indexed: 02/06/2023]
Abstract
The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti-proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti-cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post-MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure-based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.
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Affiliation(s)
- Duaa Kanan
- Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey.,Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey
| | - Tarek Kanan
- Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey.,Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey
| | - Berna Dogan
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey
| | - Muge Didem Orhan
- Neuroscience Program, Institute of Health Sciences, Bahcesehir University, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey
| | - Timucin Avsar
- Neuroscience Program, Institute of Health Sciences, Bahcesehir University, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey.,Department of Medical Biology, Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey
| | - Serdar Durdagi
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, Bahcesehir University School of Medicine, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey.,Neuroscience Program, Institute of Health Sciences, Bahcesehir University, Batman Sk. No: 66, Kadıköy, İstanbul, 34734, Turkey
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16
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Jia P, Zhang W, Xiang Y, Lu X, Liu W, Jia K, Yi M. Ubiquitin-specific protease 5 was involved in the interferon response to RGNNV in sea perch (Lateolabrax japonicus). FISH & SHELLFISH IMMUNOLOGY 2020; 103:239-247. [PMID: 32437860 DOI: 10.1016/j.fsi.2020.04.065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 03/25/2020] [Accepted: 04/29/2020] [Indexed: 06/11/2023]
Abstract
Deubiquitinases are widely involved in the regulation of the virus-triggered type I interferon (IFN) signaling. Here, we found sea perch (Lateolabrax japonicus) ubiquitin-specific protease 5 (LjUSP5) was a negative regulatory factor of the red-spotted grouper nervous necrosis virus (RGNNV)-triggered IFN response. LjUSP5 encoded a polypeptide of 830 amino acids, containing a zinc finger UBP domain (residues 197-270 aa), two ubiquitin-associated domains (residues 593-607 aa; 628-665 aa), and one UBP domain (residues 782-807 aa), and shared the closest genetic relationship with the USP5 of Larimichthys crocea. Quantitative RT-PCR analysis showed that LjUSP5 was ubiquitously expressed and up-regulated significantly in all inspected tissues post RGNNV infection, and its transcripts significantly increased in brain, liver and kidney tissues post RGNNV infection. LjUSP5 was up-regulated in cultured LJB cells after poly I:C and RGNNV treatments. In addition, overexpression of LjUSP5 significantly inhibited the activation of zebrafish IFN 1 promoter and promoted RGNNV replication in vitro. Furthermore, LjUSP5 inhibited the activation of zebrafish IFN 1 promoter induced by key genes of retinoic acid-inducible gene I-like receptors signaling pathway. Our findings provides useful information for further elucidating the mechanism underlying NNV infection.
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Affiliation(s)
- Peng Jia
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
| | - Wanwan Zhang
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
| | - Yangxi Xiang
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
| | - Xiaobing Lu
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
| | - Wei Liu
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
| | - Kuntong Jia
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
| | - Meisheng Yi
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangdong, China.
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17
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Yang L, Chen X, Yang Q, Chen J, Huang Q, Yao L, Yan D, Wu J, Zhang P, Tang D, Zhong N, Liu J. Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells. Front Oncol 2020; 10:949. [PMID: 32596160 PMCID: PMC7304060 DOI: 10.3389/fonc.2020.00949] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/14/2020] [Indexed: 01/15/2023] Open
Abstract
Proteasomal deubiquitinase (DUB) inhibition has been found to be effective in experimental cancer therapy by inducing proteasome inhibition and apoptosis. Ferroptosis is a form of regulated cell death characterized by an iron-dependent lipid peroxidation. Antioxidant enzyme glutathione peroxidase 4 (GPX4) plays a key role in blocking ferroptosis through directly reducing phospholipid hydroperoxides production. Since cytoplasmic DUB inhibition can promote protein degradation in the cell, we hypothesize that DUB inhibition induces GPX4 degradation. Here we used palladium pyrithione complex (PdPT), a broad spectrum deubiquitinase inhibitor, to explore its cell death induction and anti-cancer effect in vitro, ex vivo, and in vivo. Mechanically, caspase activation and GPX4 protein degradation are required for PdPT-induced apoptosis and ferroptosis, respectively. Notably, PdPT-induced multiple deubiquitinase inhibition is essential for proteasomal degradation of GPX4. These findings not only identify a novel mechanism of post-translational modification of GPX4 in ferroptosis, but also suggest a potential anti-caner therapeutic strategy using Pan-DUB inhibition.
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Affiliation(s)
- Li Yang
- The Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guizhou, China.,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xin Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qianqian Yang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jinghong Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qingtian Huang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Leyi Yao
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Ding Yan
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jiawen Wu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Peiquan Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Nanshan Zhong
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jinbao Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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18
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Momtaz S, Memariani Z, El-Senduny FF, Sanadgol N, Golab F, Katebi M, Abdolghaffari AH, Farzaei MH, Abdollahi M. Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases. Front Physiol 2020; 11:361. [PMID: 32411012 PMCID: PMC7199656 DOI: 10.3389/fphys.2020.00361] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and the central nervous system functionality. The ubiquitin-proteasome system (UPS) is a non-lysosomal proteolytic pathway involved in numerous normal functions of the nervous system, modulation of neurotransmitter release, synaptic plasticity, and recycling of membrane receptors or degradation of damaged and regulatory intracellular proteins. Aberrant accumulation of intracellular ubiquitin-positive inclusions has been implicated to a variety of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Myeloma (MM). Genetic mutation in deubiquitinating enzyme could disrupt UPS and results in destructive effects on neuron survival. To date, various agents were characterized with proteasome-inhibitory potential. Proteins of the ubiquitin-proteasome system, and in particular, E3 ubiquitin ligases, may be promising molecular targets for neurodegenerative drug discovery. Phytochemicals, specifically polyphenols (PPs), were reported to act as proteasome-inhibitors or may modulate the proteasome activity. PPs modify the UPS by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission. This is the first comprehensive review on the effect of PPs on UPS. Here, we review the recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders. This review attempts to summarize the latest reports on the neuroprotective properties involved in the proper functioning of natural polyphenolic compounds with implication for targeting ubiquitin-proteasome pathway in the neurodegenerative diseases. We highlight the evidence suggesting that polyphenolic compounds have a dose and disorder dependent effects in improving neurological dysfunctions, and so their mechanism of action could stimulate the UPS, induce the protein degradation or inhibit UPS and reduce protein degradation. Future studies should focus on molecular mechanisms by which PPs can interfere this complex regulatory system at specific stages of the disease development and progression.
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Affiliation(s)
- Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.,Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran, Iran
| | - Zahra Memariani
- Traditional Medicine and History of Medical Sciences Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | | | - Nima Sanadgol
- Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran.,Department of Biomolecular Sciences, School of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, Brazil
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Science, Tehran, Iran
| | - Majid Katebi
- Department of Anatomy, Faculty of Medicine, Hormozgan University of Medical Sciences, Hormozgan, Iran
| | - Amir Hossein Abdolghaffari
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.,Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran, Iran.,Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Abdollahi
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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19
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Gu C, Yin Z, Nie H, Liu Y, Yang J, Huang G, Shen J, Chen L, Fei J. Identification of berberine as a novel drug for the treatment of multiple myeloma via targeting UHRF1. BMC Biol 2020; 18:33. [PMID: 32213189 PMCID: PMC7098108 DOI: 10.1186/s12915-020-00766-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 03/05/2020] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM. RESULTS Here, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity. CONCLUSIONS In summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.
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Affiliation(s)
- Chunming Gu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou, 510632, China
- Institute of Chinese Integrative Medicine, Chinese Medicine College, Jinan University, Guangzhou, 510632, China
| | - Zhao Yin
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou, 510632, China
- Institute of Chinese Integrative Medicine, Chinese Medicine College, Jinan University, Guangzhou, 510632, China
| | - Hong Nie
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Yanjun Liu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou, 510632, China
| | - Juhua Yang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou, 510632, China
| | - Guiping Huang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou, 510632, China
| | - Jianping Shen
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China.
| | - Liguo Chen
- Institute of Chinese Integrative Medicine, Chinese Medicine College, Jinan University, Guangzhou, 510632, China.
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou, 510632, China.
- Institute of Chinese Integrative Medicine, Chinese Medicine College, Jinan University, Guangzhou, 510632, China.
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20
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The role of deubiquitinating enzymes in cancer drug resistance. Cancer Chemother Pharmacol 2020; 85:627-639. [PMID: 32146496 DOI: 10.1007/s00280-020-04046-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 02/19/2020] [Indexed: 12/18/2022]
Abstract
Drug resistance is a well-known phenomenon leading to a reduction in the effectiveness of pharmaceutical treatments. Resistance to chemotherapeutic agents can involve various intrinsic cellular processes including drug efflux, increased resistance to apoptosis, increased DNA damage repair capabilities in response to platinum salts or other DNA-damaging drugs, drug inactivation, drug target alteration, epithelial-mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic effects, or any combination of these mechanisms. Deubiquitinating enzymes (DUBs) reverse ubiquitination of target proteins, maintaining a balance between ubiquitination and deubiquitination of proteins to maintain cell homeostasis. Increasing evidence supports an association of altered DUB activity with development of several cancers. Thus, DUBs are promising candidates for targeted drug development. In this review, we outline the involvement of DUBs, particularly ubiquitin-specific proteases, and their roles in drug resistance in different types of cancer. We also review potential small molecule DUB inhibitors that can be used as drugs for cancer treatment.
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21
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Meng X, Xiong Z, Xiao W, Yuan C, Wang C, Huang Y, Tong J, Shi J, Chen Z, Liu C, Xie K, Xiong H, Chen K, Yang H, Zhang X. Downregulation of ubiquitin-specific protease 2 possesses prognostic and diagnostic value and promotes the clear cell renal cell carcinoma progression. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:319. [PMID: 32355763 PMCID: PMC7186618 DOI: 10.21037/atm.2020.02.141] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Clear cell renal cell carcinoma (ccRCC), characterized by high mortality, invasion, metastasis, recurrence and drug resistance, is the most common malignant tumor of the urinary system. A clear understanding of the underlying molecular mechanisms and its role during tumorigenesis of RCC can contribute to development of prognostic and targeted therapies. Methods We analyzed datasets from the public database, TCGA, Oncomine, for differential expression of ubiquitin-specific protease 2 (USP2), and further investigated its relationship with the clinical stage, pathological grade and prognosis of renal cancer. We used real-time quantitative PCR and western blot analysis to validate USP2 expression in clinical samples and renal cancer cell lines. Finally, we used CCK-8 and transwell assays to determine its effects on biological functions in cells. Results We observed significantly lower levels of USP2 mRNA in renal cancer, relative to normal, tissues across the four datasets from the Oncomine database (P<0.001), 533 cases from TCGA database (P<0.0001) and 30 pairs of clinical samples (P<0.0001). Similarly, a decreased USP2 protein expression in ccRCC was detected following immunohistochemical (IHC) and western blot analyses. Furthermore, the aberrant expression of USP2 resulted in significant relationship with clinical stage, pathological grade and lower USP2 mRNA expression was interrelated to poor prognosis of renal cell carcinoma. USP2 acted as an independent factor for ccRCC diagnosis, with an AUC of 0.8888 (95% CI: 0.8529 to 0.9246; P<0.0001). Exogenous restoration of USP2 in ccRCC cells resulted in repression of cell proliferation, migration, and invasion. Conclusions Overall, these results show that USP2 acts as an anti-oncogene and an independent factor for ccRCC prognosis. Positive modulation of USP2 might lead to development of a novel strategy for ccRCC treatment.
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Affiliation(s)
- Xiangui Meng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhiyong Xiong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wen Xiao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Changfei Yuan
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cheng Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Huang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Junwei Tong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jian Shi
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhixian Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chenchen Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kairu Xie
- Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hailong Xiong
- Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ke Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hongmei Yang
- Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Luo Y, Tian Z, Hua X, Huang M, Xu J, Li J, Huang H, Cohen M, Huang C. Isorhapontigenin (ISO) inhibits stem cell-like properties and invasion of bladder cancer cell by attenuating CD44 expression. Cell Mol Life Sci 2020; 77:351-363. [PMID: 31222373 PMCID: PMC6923629 DOI: 10.1007/s00018-019-03185-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/20/2019] [Accepted: 06/06/2019] [Indexed: 12/21/2022]
Abstract
Cancer stem cells (CSC) are highly associated with poor prognosis in cancer patients. Our previous studies report that isorhapontigenin (ISO) down-regulates SOX2-mediated cyclin D1 induction and stem-like cell properties in glioma stem-like cells. The present study revealed that ISO could inhibit stem cell-like phenotypes and invasivity of human bladder cancer (BC) by specific attenuation of expression of CD44 but not SOX-2, at both the protein transcription and degradation levels. On one hand, ISO inhibited cd44 mRNA expression through decreases in Sp1 direct binding to its promoter region-binding site, resulting in attenuation of its transcription. On the other hand, ISO also down-regulated USP28 expression, which in turn reduced CD44 protein stability. Further studies showed that ISO treatment induced miR-4295, which specific bound to 3'-UTR activity of usp28 mRNA and inhibited its translation and expression, while miR-4295 induction was mediated by increased Dicer protein to enhance miR-4295 maturation upon ISO treatment. Our results provide the first evidence that ISO has a profound inhibitory effect on human BC stem cell-like phenotypes and invasivity through the mechanisms distinct from those previously noted in glioma stem-like cells.
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Affiliation(s)
- Yisi Luo
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Zhongxian Tian
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Xiaohui Hua
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Maowen Huang
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Jiheng Xu
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Jingxia Li
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Haishan Huang
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Mitchell Cohen
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Chuanshu Huang
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA.
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23
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Peng Y, Liu Y, Gao Y, Yuan B, Qi X, Fu Y, Zhu Q, Cao T, Zhang S, Yin L, Li X. USP7 is a novel Deubiquitinase sustaining PLK1 protein stability and regulating chromosome alignment in mitosis. J Exp Clin Cancer Res 2019; 38:468. [PMID: 31730000 PMCID: PMC6858727 DOI: 10.1186/s13046-019-1457-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 10/17/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. METHODS Cell viability or clonogenicity was tested by violet crystal assay. Cell apoptosis or cell cycle was analyzed by flow cytometry, and chromosome misalignment was observed by a fluorescent microscopy. The protein interaction of PLK1 and USP7 was detected by tandem affinity purification and high throughput proteomics, and further confirmed by co-immunoprecipitation, GST pull-down and protein co-localization. The correlation between USP7 level of tumor tissues and taxane-resistance was evaluated. RESULTS Pharmacological USP7 inhibition by P5091 retarded cell proliferation and induced cell apoptosis. Further studies showed that P5091 induced cell cycle arrest at G2/M phase, and particularly induced chromosome misalignment, indicating the key roles of USP7 in mitosis. USP7 protein was detected in the PLK1-interacted protein complex. USP7 interacts with PLK1 protein through its PBD domain by catalytic activity. USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway. By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival. Both USP7 and PLK1 were overexpressed in taxane-resistant cancer cells, and negatively correlated with the MP scores in tumor tissues. Either USP7 or PLK1 knockdown by RNAi significantly sensitized taxane-resistant cells to taxane cell killing. CONCLUSION This is the first report that PLK1 is a novel substrate of USP7 deubiquitinase, and that USP7 sustained the protein stability of PLK1. USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.
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Affiliation(s)
- Yuchong Peng
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Youhong Liu
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Yingxue Gao
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Bowen Yuan
- Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xuli Qi
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Yuxin Fu
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Qianling Zhu
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Tuoyu Cao
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Songwei Zhang
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Linglong Yin
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiong Li
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China
- School of Clinical Pharmacy, Guangdong Pharmacology University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Pharmacology University, 19 Nonglinxia Road, Yuexiu District, Guangzhou, Guangdong China
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24
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Wertz IE, Murray JM. Structurally-defined deubiquitinase inhibitors provide opportunities to investigate disease mechanisms. DRUG DISCOVERY TODAY. TECHNOLOGIES 2019; 31:109-123. [PMID: 31200854 DOI: 10.1016/j.ddtec.2019.02.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 12/17/2022]
Abstract
The Ubiquitin/Proteasome System comprises an essential cellular mechanism for regulated protein degradation. Ubiquitination may also promote the assembly of protein complexes that initiate intracellular signaling cascades. Thus, proper regulation of substrate protein ubiquitination is essential for maintaining normal cellular physiology. Deubiquitinases are the class of enzymes responsible for removing ubiquitin modifications from target proteins and have been implicated in regulating human disease. As such, deubiquitinases are now recognized as emerging drug targets. Small molecule deubiquitinase inhibitors have been developed; among those, inhibitors for the deubiquitinases USP7 and USP14 are the best-characterized given that they are structurally validated. In this review we discuss the normal physiological roles of the USP7 and USP14 deubiquitinases as well as the pathological conditions associated with their dysfunction, with a focus on oncology and neurodegenerative diseases. We also review structural biology of USP7 and USP14 enzymes and the characterization of their respective inhibitors, highlighting the various molecular mechanisms by which these deubiquitinases may be functionally inhibited. Finally, we summarize the cellular and in vivo studies performed using the structurally-validated USP7 and USP14 inhibitors.
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Affiliation(s)
- Ingrid E Wertz
- Department of Discovery Oncology, Genentech, Inc. 1 DNA Way, South San Francisco, 94080, USA; Department of Early Discovery Biochemistry, Genentech, Inc. 1 DNA Way, South San Francisco, 94080, USA.
| | - Jeremy M Murray
- Department of Structural Biology, Genentech, Inc. 1 DNA Way, South San Francisco, 94080, USA.
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25
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Woo SM, Kwon TK. E3 ubiquitin ligases and deubiquitinases as modulators of TRAIL-mediated extrinsic apoptotic signaling pathway. BMB Rep 2019. [PMID: 30638181 PMCID: PMC6443324 DOI: 10.5483/bmbrep.2019.52.2.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression. [BMB Reports 2019; 52(2): 119-126].
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Affiliation(s)
- Seon Min Woo
- Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea
| | - Taeg Kyu Kwon
- Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea
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26
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USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis. Oncogene 2018; 38:2405-2419. [DOI: 10.1038/s41388-018-0590-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 10/18/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023]
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27
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USP49 participates in the DNA damage response by forming a positive feedback loop with p53. Cell Death Dis 2018; 9:553. [PMID: 29748582 PMCID: PMC5945681 DOI: 10.1038/s41419-018-0475-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 02/26/2018] [Accepted: 03/07/2018] [Indexed: 12/21/2022]
Abstract
The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. In our study, we identified USP49 as a novel deubiquitinase (DUB) for p53 from a library consisting of 80 DUBs and found that USP49 has a positive effect on p53 transcriptional activity and protein stability. Investigation of the mechanism revealed that USP49 interacts with the N terminus of p53 and suppresses several types of p53 ubiquitination. Furthermore, USP49 rendered HCT116 cells more sensitive to etoposide (Eto)-induced DNA damage and was upregulated in response to several types of cell stress, including DNA damage. Remarkably, USP49 expression was regulated by p53 and USP49 in knockout mice, which are more susceptible to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors. These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53.
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28
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Chen X, Yang Q, Xiao L, Tang D, Dou QP, Liu J. Metal-based proteasomal deubiquitinase inhibitors as potential anticancer agents. Cancer Metastasis Rev 2018; 36:655-668. [PMID: 29039082 PMCID: PMC5721122 DOI: 10.1007/s10555-017-9701-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate proteins. Therefore, recent findings have focused on the relevance of DUBs to cancer development, and pharmacological intervention on these enzymes has become a promising strategy for cancer therapy. In particular, several DUBs are physically and/or functionally associated with the proteasome and are attractive targets for the development of novel anticancer drugs. The successful clinical application of cisplatin in cancer treatment has prompted researchers to develop various metal-based anticancer agents with new properties. Recently, we have reported that several metal-based drugs, such as the antirheumatic gold agent auranofin (AF), the antifouling paint biocides copper pyrithione (CuPT) and zinc pyrithione (ZnPT), and also our two synthesized complexes platinum pyrithione (PtPT) and nickel pyrithione (NiPT), can target the proteasomal DUBs UCHL5 and USP14. In this review, we summarize the recently reported small molecule inhibitors of proteasomal DUBs, with a focus on discussion of the unique nature of metal-based proteasomal DUB inhibitors and their anticancer activity.
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Affiliation(s)
- Xin Chen
- Protein Modification and Degradation Lab, School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qianqian Yang
- Protein Modification and Degradation Lab, School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lu Xiao
- Protein Modification and Degradation Lab, School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China
| | - Daolin Tang
- Protein Modification and Degradation Lab, School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Q Ping Dou
- Protein Modification and Degradation Lab, School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China.,The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, USA.,Department of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI, 48201-2013, USA
| | - Jinbao Liu
- Protein Modification and Degradation Lab, School of Basic Medical Sciences, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China.
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29
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Nyati S, Chaudhry N, Chatur A, Gregg BS, Kimmel L, Khare D, Basrur V, Ray D, Rehemtulla A. A novel reporter for real-time, quantitative imaging of AKT-directed K63-poly-ubiquitination in living cells. Oncotarget 2018. [PMID: 29541398 PMCID: PMC5834254 DOI: 10.18632/oncotarget.24323] [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] [Indexed: 11/30/2022] Open
Abstract
Post-translational K63-linked poly-ubiquitination of AKT is required for its membrane recruitment and phosphorylation dependent activation in response to growth-factor stimulation. Current assays for target specific poly-ubiquitination involve cumbersome enzymatic preparations and semi-quantitative readouts. We have engineered a reporter that can quantitatively and in a target specific manner report on AKT-directed K63-polyubiquitination (K63UbR) in live cells. The reporter constitutes the AKT-derived poly-ubiquitination substrate peptide, a K63 poly-ubiquitin binding domain (UBD) as well as the split luciferase protein complementation domains. In cells, wherein signaling events upstream of AKT are activated (e.g. either EGFR or IGFR), poly-ubiquitination of the reporter leads to a stearic constraint that prevents luciferase complementation. However, upon inhibition of growth factor receptor signaling, loss of AKT poly-ubiquitination results in a decrease in interaction between the target peptide and the UBD, allowing for reconstitution of the split luciferase domains and therefore increased bioluminescence in a quantitative and dynamic manner. The K63UbR was confirmed to be suitable for high throughput screen (HTS), thus providing an excellent tool for small molecule or siRNA based HTS to discover new inhibitors or identify novel regulators of this key signaling node. Furthermore, the K63UbR platform could be adapted for non-invasive monitoring of additional target specific K63-polyubiquitination events in live cells.
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Affiliation(s)
- Shyam Nyati
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Nauman Chaudhry
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Areeb Chatur
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Brandon S Gregg
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Lauren Kimmel
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Dheeraj Khare
- Life Sciences Institute, University of Michigan, Ann Arbor, MI-48109, USA
| | - Venkatesha Basrur
- UMCCC Proteomics Shared Resource, University of Michigan, Ann Arbor, MI-48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Dipankar Ray
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
| | - Alnawaz Rehemtulla
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI-48109, USA
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30
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Gopinath P, Ohayon S, Nawatha M, Brik A. Chemical and semisynthetic approaches to study and target deubiquitinases. Chem Soc Rev 2018; 45:4171-98. [PMID: 27049734 DOI: 10.1039/c6cs00083e] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Ubiquitination is a key posttranslational modification, which affects numerous biological processes and is reversed by a class of enzymes known as deubiquitinases (DUBs). This family of enzymes cleaves mono-ubiquitin or poly-ubiquitin chains from a target protein through different mechanisms and mode of interactions with their substrates. Studying the role of DUBs in health and diseases has been a major goal for many laboratories both in academia and in industry. However, the field has been challenged by the difficulties in obtaining native substrates and novel reagents using traditional enzymatic and molecular biology approaches. Recent advancements in the synthesis and semisynthesis of proteins made it possible to prepare several unique ubiquitin conjugates to study various aspects of DUBs such as their specificities and structures. Moreover, these approaches enable the preparation of novel activity based probes and assays to monitor DUB activities in vitro and in cellular contexts. Efforts made to bring new chemical entities for the selective inhibition of DUBs based on these tools are also highlighted with selected examples.
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Affiliation(s)
- Pushparathinam Gopinath
- Schulich Faculty of Chemistry, Technion-Israel Institute of Technology Haifa, 3200008, Israel.
| | - Shimrit Ohayon
- Schulich Faculty of Chemistry, Technion-Israel Institute of Technology Haifa, 3200008, Israel.
| | - Mickal Nawatha
- Schulich Faculty of Chemistry, Technion-Israel Institute of Technology Haifa, 3200008, Israel.
| | - Ashraf Brik
- Schulich Faculty of Chemistry, Technion-Israel Institute of Technology Haifa, 3200008, Israel.
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31
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Wrigley JD, Gavory G, Simpson I, Preston M, Plant H, Bradley J, Goeppert AU, Rozycka E, Davies G, Walsh J, Valentine A, McClelland K, Odrzywol KE, Renshaw J, Boros J, Tart J, Leach L, Nowak T, Ward RA, Harrison T, Andrews DM. Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily. ACS Chem Biol 2017; 12:3113-3125. [PMID: 29131570 DOI: 10.1021/acschembio.7b00334] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to targeting this so far undruggable oncogene. Here, we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and while displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases (DUBs). The utility of these compounds as valuable probes to investigate and further explore cellular DUB biology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal cell lines. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets.
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Affiliation(s)
- Jonathan D. Wrigley
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Gerald Gavory
- Almac Discovery Ltd., Centre for Precision
Therapeutics, 97 Lisburn
Road, Belfast, BT9 7AE, United Kingdom
| | - Iain Simpson
- Oncology,
IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Marian Preston
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Helen Plant
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Jenna Bradley
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Anne U. Goeppert
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Ewelina Rozycka
- Almac Discovery Ltd., Centre for Precision
Therapeutics, 97 Lisburn
Road, Belfast, BT9 7AE, United Kingdom
| | - Gareth Davies
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Jarrod Walsh
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Andrea Valentine
- Almac Discovery Ltd., Centre for Precision
Therapeutics, 97 Lisburn
Road, Belfast, BT9 7AE, United Kingdom
| | - Keeva McClelland
- Almac Discovery Ltd., Centre for Precision
Therapeutics, 97 Lisburn
Road, Belfast, BT9 7AE, United Kingdom
| | - Krzysztofa Ewa Odrzywol
- Almac Discovery Ltd., Centre for Precision
Therapeutics, 97 Lisburn
Road, Belfast, BT9 7AE, United Kingdom
| | - Jonathan Renshaw
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Joanna Boros
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Jonathan Tart
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Lindsey Leach
- Discovery
Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Thorsten Nowak
- Oncology,
IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Richard A. Ward
- Oncology,
IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Timothy Harrison
- Almac Discovery Ltd., Centre for Precision
Therapeutics, 97 Lisburn
Road, Belfast, BT9 7AE, United Kingdom
| | - David M. Andrews
- Oncology,
IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
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32
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Abstract
Although growing numbers of oncoproteins and pro-metastatic proteins have been extensively characterized, many of these tumor-promoting proteins are not good drug targets, which represent a major barrier to curing breast cancer and other cancers. There is a need, therefore, for alternative therapeutic approaches to destroying cancer-promoting proteins. The human genome encodes approximately 100 deubiquitinating enzymes (DUBs, also called deubiquitinases), which are amenable to pharmacologic inhibition by small molecules. By removing monoubiquitin or polyubiquitin chains from the target protein, DUBs can modulate the degradation, localization, activity, trafficking, and recycling of the substrate, thereby contributing substantially to the regulation of cancer proteins and pathways. Targeting certain DUBs may lead to destabilization or functional inactivation of some key oncoproteins or pro-metastatic proteins, including non-druggable ones, which will provide therapeutic benefits to cancer patients. In breast cancer, growing numbers of DUBs are found to be aberrantly expressed. Depending on their substrates, specific DUBs can either promote or suppress mammary tumors. In this article, we review the role and mechanisms of action of DUBs in breast cancer and discuss the potential of targeting DUBs for cancer treatment.
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33
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Setz C, Friedrich M, Rauch P, Fraedrich K, Matthaei A, Traxdorf M, Schubert U. Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes. Viruses 2017; 9:v9080222. [PMID: 28805676 PMCID: PMC5580479 DOI: 10.3390/v9080222] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 08/04/2017] [Accepted: 08/08/2017] [Indexed: 12/18/2022] Open
Abstract
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells.
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Affiliation(s)
- Christian Setz
- Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
| | - Melanie Friedrich
- Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
| | - Pia Rauch
- Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
| | - Kirsten Fraedrich
- Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
| | - Alina Matthaei
- Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
| | - Maximilian Traxdorf
- Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
| | - Ulrich Schubert
- Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
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Jiang L, Xiong J, Zhan J, Yuan F, Tang M, Zhang C, Cao Z, Chen Y, Lu X, Li Y, Wang H, Wang L, Wang J, Zhu WG, Wang H. Ubiquitin-specific peptidase 7 (USP7)-mediated deubiquitination of the histone deacetylase SIRT7 regulates gluconeogenesis. J Biol Chem 2017; 292:13296-13311. [PMID: 28655758 DOI: 10.1074/jbc.m117.780130] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 06/26/2017] [Indexed: 12/13/2022] Open
Abstract
Sirtuin 7 (SIRT7), a member of the NAD+-dependent class III histone deacetylases, is involved in the regulation of various cellular processes and in resisting various stresses, such as hypoxia, low glucose levels, and DNA damage. Interestingly, SIRT7 is linked to the control of glycolysis, suggesting a role in glucose metabolism. Given the important roles of SIRT7, it is critical to clarify how SIRT7 activity is potentially regulated. It has been reported that some transcriptional and post-transcriptional regulatory mechanisms are involved. However, little is known how SIRT7 is regulated by the post-translational modifications. Here, we identified ubiquitin-specific peptidase 7 (USP7), a deubiquitinase, as a negative regulator of SIRT7. We showed that USP7 interacts with SIRT7 both in vitro and in vivo, and we further demonstrated that SIRT7 undergoes endogenous Lys-63-linked polyubiquitination, which is removed by USP7. Although the USP7-mediated deubiquitination of SIRT7 had no effect on its stability, the deubiquitination repressed its enzymatic activity. We also showed that USP7 coordinates with SIRT7 to regulate the expression of glucose-6-phosphatase catalytic subunit (G6PC), a gluconeogenic gene. USP7 depletion by RNA interference increased both G6PC expression and SIRT7 enzymatic activity. Moreover, SIRT7 targeted the G6PC promoter through the transcription factor ELK4 but not through forkhead box O1 (FoxO1). In summary, SIRT7 is a USP7 substrate and has a novel role as a regulator of gluconeogenesis. Our study may provide the basis for new clinical approaches to treat metabolic disorders related to glucose metabolism.
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Affiliation(s)
- Lu Jiang
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Jiannan Xiong
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Junsi Zhan
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Fengjie Yuan
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Ming Tang
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Chaohua Zhang
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Ziyang Cao
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Yongcan Chen
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Xiaopeng Lu
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Yinglu Li
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Hui Wang
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Lina Wang
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center
| | - Jiadong Wang
- Institute of Systems Biomedicine, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191 and
| | - Wei-Guo Zhu
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, .,Peking-Tsinghua University Center for Life Science, and.,the Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China
| | - Haiying Wang
- From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center,
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Sun Y, Cao L, Sheng X, Chen J, Zhou Y, Yang C, Deng T, Ma H, Feng P, Liu J, Tan W, Ye M. WDR79 promotes the proliferation of non-small cell lung cancer cells via USP7-mediated regulation of the Mdm2-p53 pathway. Cell Death Dis 2017; 8:e2743. [PMID: 28406480 PMCID: PMC5477585 DOI: 10.1038/cddis.2017.162] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 03/02/2017] [Accepted: 03/13/2017] [Indexed: 12/26/2022]
Abstract
WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family and functions as a scaffold protein during telomerase assembly, Cajal body formation and DNA double strand break repair. We have previously shown that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC) and it accelerates cell proliferation in NSCLC. However, the detailed mechanism underlying the role of WDR79 in the proliferation of NSCLC cells remains unclear. Here, we report the discovery of a molecular interaction between WDR79 and USP7 and show its functional significance in linking the Mdm2-p53 pathway to the proliferation of NSCLC cells. We found that WDR79 colocalized and interacted with USP7 in the nucleus of NSCLC cells. This event, in turn, reduced the ubiquitination of Mdm2 and p53, thereby increasing the stability and extending the half-life of the two proteins. We further found that the functional effects of WDR79 depended upon USP7, because the knockdown of USP7 resulted in their attenuation. Finally, we demonstrated that WDR79 promoted the proliferation of NSCLC cells via USP7. Taken together, our findings reveal a novel molecular function of WDR79 and may lead to broadly applicable and innovative therapeutic avenues for NSCLC.
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Affiliation(s)
- Yang Sun
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Lanqin Cao
- Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China
| | - Xunan Sheng
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Jieying Chen
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Yu Zhou
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Chao Yang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China.,College of Life and Environmental Sciences, Gannan Normal University, Ganzhou, Jiangxi 341000, China
| | - Tanggang Deng
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Hongchang Ma
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Peifu Feng
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Jing Liu
- School of Life Sciences, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China
| | - Weihong Tan
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
| | - Mao Ye
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China
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Wu Y, Wang Y, Lin Y, Liu Y, Wang Y, Jia J, Singh P, Chi YI, Wang C, Dong C, Li W, Tao M, Napier D, Shi Q, Deng J, Mark Evers B, Zhou BP. Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation. Nat Commun 2017; 8:14228. [PMID: 28198361 PMCID: PMC5316870 DOI: 10.1038/ncomms14228] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 11/30/2016] [Indexed: 12/27/2022] Open
Abstract
Snail1, a key transcription factor of epithelial-mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitro and in vivo. Our study reveals a critical Dub3-Snail1 signalling axis in EMT and metastasis, and provides an effective therapeutic approach against breast cancer.
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Affiliation(s)
- Yadi Wu
- Department of Pharmacology & Nutritional Sciences, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Yu Wang
- Department of Pharmacology & Nutritional Sciences, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Yiwei Lin
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Yajuan Liu
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Yifan Wang
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Jianhang Jia
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Puja Singh
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
| | - Young-In Chi
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
| | - Chi Wang
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Biostatistics, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Chenfang Dong
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Zhejiang 310058, China
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou 215006, China
| | - Min Tao
- Department of Oncology, The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou 215006, China
| | - Dana Napier
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Pathology, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Qiuying Shi
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Pathology, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Jiong Deng
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - B Mark Evers
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Surgery, the University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
| | - Binhua P. Zhou
- Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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37
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Chen X, Wu J, Chen Y, Ye D, Lei H, Xu H, Yang L, Wu Y, Gu W. Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma. Int J Biochem Cell Biol 2016; 79:350-359. [PMID: 27592452 DOI: 10.1016/j.biocel.2016.08.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 08/10/2016] [Accepted: 08/29/2016] [Indexed: 01/26/2023]
Abstract
Ubiquitin-specific protease 14, a deubiquitinating enzyme, has been implicated in the tumorigenesis and progression of several cancers, but its role in oral squamous cell carcinoma remains to be elucidated. The aim of this study was to explore the expression pattern and roles of Ubiquitin-specific protease 14 in the occurrence and development of oral squamous cell carcinoma. Interestingly, Ubiquitin-specific protease 14 was overexpressed in oral cancer tissues and cell lines at both mRNA and protein levels. b-AP15, a specific inhibitor of Ubiquitin-specific protease 14, significantly inhibited the growth of cancer cells and increased cell apoptosis in a dose-dependent manner. Moreover, knockdown of Ubiquitin-specific protease 14 by shRNA significantly inhibited the proliferation and migration of cancer cells in vitro. Finally, using a xenograft mouse model of oral squamous cell carcinoma, knockdown of Ubiquitin-specific protease 14 markedly inhibited tumor growth and triggered the cancer cell apoptosis in vivo, supporting previous results. In conclusion, for the first time we have demonstrated the expression pattern of Ubiquitin-specific protease 14 in oral squamous cell carcinoma and verified a relationship with tumor growth and metastasis. These results may highlight new therapeutic strategies for tumor treatment, application of Ubiquitin-specific protease 14 selective inhibitor, such as b-AP15, or knockdown by shRNA. Collectively, Ubiquitin-specific protease 14 could be a potential therapeutic target for oral squamous cell carcinoma patients.
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Affiliation(s)
- Xiangyun Chen
- Department of Clinical Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jingjing Wu
- Department of Clinical Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yitian Chen
- Department of Clinical Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Dongxia Ye
- Shanghai Research Institute of Stomatology, Shanghai 200011, China
| | - Hu Lei
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hanzhang Xu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li Yang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yingli Wu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Wenli Gu
- Department of Clinical Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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Zou T, Zhang JJ, Cao B, Tong KC, Lok CN, Che CM. Deubiquitinases as Anticancer Targets of Gold Complexes. Isr J Chem 2016. [DOI: 10.1002/ijch.201600044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Taotao Zou
- State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry; The University of Hong Kong; Pokfulam Road Hong Kong S.A.R.P.R. China
- HKU Shenzhen Institute of Research and Innovation; Shenzhen 518053 P.R. China
| | - Jing-Jing Zhang
- State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry; The University of Hong Kong; Pokfulam Road Hong Kong S.A.R.P.R. China
| | - Bei Cao
- State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry; The University of Hong Kong; Pokfulam Road Hong Kong S.A.R.P.R. China
| | - Ka-Chung Tong
- State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry; The University of Hong Kong; Pokfulam Road Hong Kong S.A.R.P.R. China
| | - Chun-Nam Lok
- State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry; The University of Hong Kong; Pokfulam Road Hong Kong S.A.R.P.R. China
| | - Chi-Ming Che
- State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry; The University of Hong Kong; Pokfulam Road Hong Kong S.A.R.P.R. China
- HKU Shenzhen Institute of Research and Innovation; Shenzhen 518053 P.R. China
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Pinto-Fernandez A, Kessler BM. DUBbing Cancer: Deubiquitylating Enzymes Involved in Epigenetics, DNA Damage and the Cell Cycle As Therapeutic Targets. Front Genet 2016; 7:133. [PMID: 27516771 PMCID: PMC4963401 DOI: 10.3389/fgene.2016.00133] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 07/12/2016] [Indexed: 12/21/2022] Open
Abstract
Controlling cell proliferation is one of the hallmarks of cancer. A number of critical checkpoints ascertain progression through the different stages of the cell cycle, which can be aborted when perturbed, for instance by errors in DNA replication and repair. These molecular checkpoints are regulated by a number of proteins that need to be present at the right time and quantity. The ubiquitin system has emerged as a central player controlling the fate and function of such molecules such as cyclins, oncogenes and components of the DNA repair machinery. In particular, proteases that cleave ubiquitin chains, referred to as deubiquitylating enzymes (DUBs), have attracted recent attention due to their accessibility to modulation by small molecules. In this review, we describe recent evidence of the critical role of DUBs in aspects of cell cycle checkpoint control, associated DNA repair mechanisms and regulation of transcription, representing pathways altered in cancer. Therefore, DUBs involved in these processes emerge as potentially critical targets for the treatment of not only hematological, but potentially also solid tumors.
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Affiliation(s)
- Adan Pinto-Fernandez
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford Oxford, UK
| | - Benedikt M Kessler
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford Oxford, UK
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Abstract
Deubiquitinases are deubiquitinating enzymes (DUBs), which remove ubiquitin from proteins, thus regulating their proteasomal degradation, localization and activity. Here, we discuss DUBs as anti-cancer drug targets.
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Meng Y, Zhang C, Yi J, Zhou Z, Fa Z, Zhao J, Yang Y, Fang W, Wang Y, Liao WQ. Deubiquitinase Ubp5 Is Required for the Growth and Pathogenicity of Cryptococcus gattii. PLoS One 2016; 11:e0153219. [PMID: 27049762 PMCID: PMC4822882 DOI: 10.1371/journal.pone.0153219] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 03/24/2016] [Indexed: 12/19/2022] Open
Abstract
Cryptococcus gattii is a resurgent fungal pathogen that primarily infects immunocompetent hosts. Thus, it poses an increasingly significant impact on global public health; however, the mechanisms underlying its pathogenesis remain largely unknown. We conducted a detailed characterization of the deubiquitinase Ubp5 in the biology and virulence of C. gattii using the hypervirulent strain R265, and defined its properties as either distinctive or shared with C. neoformans. Deletion of the C. gattii Ubp5 protein by site-directed disruption resulted in a severe growth defect under both normal and stressful conditions (such as high temperature, high salt, cell wall damaging agents, and antifungal agents), similar to the effects observed in C. neoformans. However, unlike C. neoformans, the C. gattii ubp5Δ mutant displayed a slight enhancement of capsule and melanin production, indicating the evolutionary convergence and divergence of Ubp5 between these two sibling species. Attenuated virulence of the Cg-ubp5Δ mutant was not solely due to its reduced thermotolerance at 37°C, as shown in both worm and mouse survival assays. In addition, the assessment of fungal burden in mammalian organs further indicated that Ubp5 was required for C. gattii pulmonary survival and, consequently, extrapulmonary dissemination. Taken together, our work highlights the importance of deubiquitinase Ubp5 in the virulence composite of both pathogenic cryptococcal species, and it facilitates a better understanding of C. gattii virulence mechanisms.
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Affiliation(s)
- Yunfang Meng
- Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Second Military Medical University, Shanghai, China.,Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Chao Zhang
- PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China
| | - Jiu Yi
- PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China
| | - Zhaojing Zhou
- PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China
| | - Zhenzong Fa
- PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China
| | - Jingyu Zhao
- Shanghai Dermatology Hospital, Shanghai, China
| | - Yali Yang
- PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China
| | - Wei Fang
- PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China
| | - Yan Wang
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Wan-Qing Liao
- Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Second Military Medical University, Shanghai, China
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Lub S, Maes K, Menu E, De Bruyne E, Vanderkerken K, Van Valckenborgh E. Novel strategies to target the ubiquitin proteasome system in multiple myeloma. Oncotarget 2016; 7:6521-37. [PMID: 26695547 PMCID: PMC4872730 DOI: 10.18632/oncotarget.6658] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 11/23/2015] [Indexed: 12/20/2022] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of plasma cells in the bone marrow (BM). The success of the proteasome inhibitor bortezomib in the treatment of MM highlights the importance of the ubiquitin proteasome system (UPS) in this particular cancer. Despite the prolonged survival of MM patients, a significant amount of patients relapse or become resistant to therapy. This underlines the importance of the development and investigation of novel targets to improve MM therapy. The UPS plays an important role in different cellular processes by targeted destruction of proteins. The ubiquitination process consists of enzymes that transfer ubiquitin to proteins targeting them for proteasomal degradation. An emerging and promising approach is to target more disease specific components of the UPS to reduce side effects and overcome resistance. In this review, we will focus on different components of the UPS such as the ubiquitin activating enzyme E1, the ubiquitin conjugating enzyme E2, the E3 ubiquitin ligases, the deubiquitinating enzymes (DUBs) and the proteasome. We will discuss their role in MM and the implications in drug discovery for the treatment of MM.
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Affiliation(s)
- Susanne Lub
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ken Maes
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Eline Menu
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Elke De Bruyne
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Karin Vanderkerken
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Els Van Valckenborgh
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
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Jian F, Cao Y, Bian L, Sun Q. USP8: a novel therapeutic target for Cushing's disease. Endocrine 2015; 50:292-6. [PMID: 26162929 DOI: 10.1007/s12020-015-0682-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 07/03/2015] [Indexed: 01/10/2023]
Abstract
Cushing's disease (CD), caused by an adrenocorticotropin-secreting pituitary adenoma, leads to hypercortisolemia and causes serious morbidity and increased mortality when suboptimally treated. Currently, the genetic events have rarely been reported in this disease. Recently, the recurrent activating mutations in the gene encoding ubiquitin-specific protease 8 (USP8) in CD have been independently reported by two teams. These hotspot mutations sustain epidermal growth factor receptor (EGFR) signaling and expand the pathogenic role of USP8 in corticotroph adenoma. This review summarizes current knowledge of USP8 and its substrate EGFR in cancer therapy and possible application of them in CD.
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Affiliation(s)
- Fangfang Jian
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China
| | - Yanan Cao
- Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Liuguan Bian
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China.
| | - Qingfang Sun
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China.
- Department of Neurosurgery, Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, No. 149, South Chongqing Road, Shanghai, 200025, China.
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Qin J, Zhou Z, Chen W, Wang C, Zhang H, Ge G, Shao M, You D, Fan Z, Xia H, Liu R, Chen C. BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5. Nat Commun 2015; 6:8471. [PMID: 26419610 PMCID: PMC4598844 DOI: 10.1038/ncomms9471] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Here we show that, in breast cancer cells, KLF5 is stabilized by the deubiquitinase (DUB) BAP1. With a genome-wide siRNA library screen of DUBs, we identify BAP1 as a bona fide KLF5 DUB. BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5. Collectively, our findings not only identify BAP1 as the DUB for KLF5, but also reveal a critical mechanism that regulates KLF5 expression in breast cancer. Our findings indicate that BAP1 could be a potential therapeutic target for breast and other cancers. The zinc finger-containing transcription factor KLF5 drives cell proliferation and migration. Here, the authors show that the debuquitinase BAP1 directly stabilizes KLF5, thus promoting basal-like breast cancer cell-cycle progression and metastasis.
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Affiliation(s)
- Junying Qin
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.,Graduate School of the Chinese Academy of Sciences, Beijing 100039, China
| | - Zhongmei Zhou
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China
| | - Wenlin Chen
- Department of Breast Surgery, Breast Cancer Clinical Research Center, Cancer Hospital, Kunming Medical University, Kunming, Yunnan 650031, China
| | - Chunyan Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.,Graduate School of the Chinese Academy of Sciences, Beijing 100039, China.,Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Hailin Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China
| | - Guangzhe Ge
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.,Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Ming Shao
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.,Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Dingyun You
- Kunming Medical University, Kunming, Yunnan 650031, China
| | - Zhixiang Fan
- Kunming Medical University, Kunming, Yunnan 650031, China
| | - Houjun Xia
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China
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Farshi P, Deshmukh RR, Nwankwo JO, Arkwright RT, Cvek B, Liu J, Dou QP. Deubiquitinases (DUBs) and DUB inhibitors: a patent review. Expert Opin Ther Pat 2015; 25:1191-1208. [PMID: 26077642 DOI: 10.1517/13543776.2015.1056737] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Deubiquitinating-enzymes (DUBs) are key components of the ubiquitin-proteasome system (UPS). The fundamental role of DUBs is specific removal of ubiquitin from substrates. DUBs contribute to activation/deactivation, recycling and localization of numerous regulatory proteins, and thus play major roles in diverse cellular processes. Altered DUB activity is associated with a multitudes of pathologies including cancer. Therefore, DUBs represent novel candidates for target-directed drug development. AREAS COVERED The article is a thorough review/accounting of patented compounds targeting DUBs and stratifying/classifying the patented compounds based on: chemical-structures, nucleic-acid compositions, modes-of-action, and targeting sites. The review provides a brief background on the UPS and the involvement of DUBs. Furthermore, methods for assessing efficacy and potential pharmacological utility of DUB inhibitor (DUBi) are discussed. EXPERT OPINION The FDA's approval of the 20S proteasome inhibitors (PIs): bortezomib and carfilzomib for treatment of hematological malignancies established the UPS as an anti-cancer target. Unfortunately, many patients are inherently resistant or develop resistance to PIs. One potential strategy to combat PI resistance is targeting upstream components of the UPS such as DUBs. DUBs represent a promising potential therapeutic target due to their critical roles in various cellular processes including protein turnover, localization and cellular homeostasis. While considerable efforts have been undertaken to develop DUB modulators, significant advancements are necessary to move DUBis into the clinic.
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Affiliation(s)
- Pershang Farshi
- Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Rahul R Deshmukh
- Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA.,Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Joseph O Nwankwo
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Federal University, Ndufu-Alike Ikwo, Ebonyi State, Nigeria
| | - Richard T Arkwright
- Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA.,Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Boris Cvek
- Department of Cell Biology & Genetics, Palacky University, Slechtitelu 11, Olomouc 78371, Czech Republic
| | - Jinbao Liu
- State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China
| | - Q Ping Dou
- Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA.,Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, USA.,Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, USA.,Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA
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Jeong CH. Inhibition of Ubiquitin-specific Peptidase 8 Suppresses Growth of Gefitinib-resistant Non-small Cell Lung Cancer Cells by Inducing Apoptosis. J Cancer Prev 2015; 20:57-63. [PMID: 25853104 PMCID: PMC4384715 DOI: 10.15430/jcp.2015.20.1.57] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 02/26/2015] [Accepted: 02/26/2015] [Indexed: 01/17/2023] Open
Abstract
Background: Therapeutic approach by treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib or erlotinib to non-small cell lung cancer (NSCLC) patients has been limited due to emergence of acquired drug resistance. Our study was aimed to investigate whether the inhibition of ubiquitin-specific peptidase 8 (USP8) could be an alternative strategy capable of overcoming acquired resistance to EGFR-TKIs for treatment of NSCLCs. Methods: The anticancer effect of USP8 inhibitor was determined by testing anchorage-dependent or independent growth of gefitinib-sensitive or resistant NSCLCs. The immunoprecipitation and western blotting were conducted to check molecular interaction and signaling pathway followed by USP8 inhibition. Results: Inhibition of USP8 induced overall degradation of oncogenic receptor tyrosine kinases including EGFR and Met, leading to a suppression of anchorage-dependent or independent cell growth of gefitinib-sensitive or resistant NSCLCs. Also, treatment with the USP8 inhibitor markedly induced apoptosis in HCC827GR cells. Notably, treatment with the USP8 inhibitor was more effective in suppressing cell growth and inducing apoptosis in gefitinib-resistant HCC827GR cells than that of gefitinib-sensitive HCC827 cells. Conclusions: Inhibition of USP8 could be an effective strategy for overcoming gefitinib resistance in NSCLCs.
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Affiliation(s)
- Chul-Ho Jeong
- College of Pharmacy, Keimyung University, Daegu, Korea
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Hu J, Yang D, Zhang H, Liu W, Zhao Y, Lu H, Meng Q, Pang H, Chen X, Liu Y, Cai L. USP22 promotes tumor progression and induces epithelial-mesenchymal transition in lung adenocarcinoma. Lung Cancer 2015; 88:239-45. [PMID: 25907317 DOI: 10.1016/j.lungcan.2015.02.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 02/26/2015] [Accepted: 02/27/2015] [Indexed: 01/30/2023]
Abstract
OBJECTIVES Our previous study showed that USP22 as an oncogene may mediate cancer development and progression in NSCLC, but the underlying molecular mechanism remains uncharacterized. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in migration and invasion of the tumor cells. Thus, this study aims to determine the clinical significance and the possible roles of USP22 in EMT and progression of lung adenocarcinoma. METHODS Immunohistochemistry was used to determine the expression of USP22 in clinical samples. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated by statistical analysis. Moreover, we evaluated whether USP22 could induce EMT in cultured lung cancer cells. RESULTS The USP22 expression was positive in 76.03% of specimens and was correlated with advanced clinicopathologic classifications (differentiation, T and AJCC stages) and TGF-β1 expression (p=0.008). Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival and disease-free survival (HR, 2.060; p=0.013 and HR, 1.993; p=0.016). In vitro study revealed that USP22 can regulate proliferation and invasive properties, and induce EMT of lung adenocarcinoma cells. Moreover, USP22 may up-regulate TGF-β1 expression. CONCLUSIONS Our data indicated that USP22 may promote lung adenocarcinoma cell invasion by the induction of EMT.
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Affiliation(s)
- Jing Hu
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Dongdong Yang
- Department of Oncological Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Huijuan Zhang
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Wei Liu
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yanbin Zhao
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Hailing Lu
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Qingwei Meng
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Hui Pang
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Xuesong Chen
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Li Cai
- The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
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USP7 overexpression predicts a poor prognosis in lung squamous cell carcinoma and large cell carcinoma. Tumour Biol 2014; 36:1721-9. [PMID: 25519684 PMCID: PMC4375295 DOI: 10.1007/s13277-014-2773-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 10/23/2014] [Indexed: 01/12/2023] Open
Abstract
In non-small cell lung cancer (NSCLC), both USP7 expression and p53 gene status were reported to be an indicator of poor prognosis in adenocarcinoma patients; however, its roles and mechanisms in lung squamous cell carcinoma and large cell carcinoma need to be clarified. The USP7 expression was examined in NSCLC tumors (excluding adenocarcinoma), their corresponding non-tumorous tissues, and NSCLC cells. Then, the prognostic role of USP7 was analyzed in 110 NSCLC samples (excluding the adenocarcinoma). Finally, the roles and mechanisms of USP7 in the proliferation, metastasis, and invasion of a NSCLC cell were assessed using a specific vshRNA. The USP7 expression was higher in NSCLC tissues compared to non-tumorous samples, accordingly, the high level of USP7 was detected in NSCLC cell lines compared with HBE cell. After the USP7 downregulation, the H460 cells exhibited decreased metastasis/invasion in vitro and in vivo. The preliminary mechanism study indicated overexpression of USP7 might regulate the p53-MDM2 pathway by inducing the MDM2 de-ubiquitination and subsequent stabilization, which resulted in the upregulation of the Bad phosphorylation. Additionally, we also found that USP7 might induce cell epithelial-mesenchymal transition to enhance the cell invasive ability. Clinically, USP7 overexpression significantly correlated with malignant phenotype. Furthermore, the 5-year overall survival in patients with USP7(low) was higher than that of USP7(high). Multivariate analysis showed USP7 overexpression was an independent prognostic marker for these cancers. USP7 overexpression may regulate the survival and invasive properties of squamous cell carcinoma and large cell carcinoma cells, and may serve as a molecular target.
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Ramakrishna S, Suresh B, Baek KH. Biological functions of hyaluronan and cytokine-inducible deubiquitinating enzymes. Biochim Biophys Acta Rev Cancer 2014; 1855:83-91. [PMID: 25481051 DOI: 10.1016/j.bbcan.2014.11.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 11/12/2014] [Accepted: 11/27/2014] [Indexed: 11/26/2022]
Abstract
The modification of proteins through post-translation and degradation by the ubiquitin-proteasome system plays a pivotal role in a broad array of biological processes. Reversal of this process by deubiquitination is a central step in the maintenance and regulation of cellular homeostasis. It now appears that the regulation of ubiquitin pathways by deubiquitinating enzymes (DUBs) could be used as targets for anticancer therapy. Recent success in inducing apoptosis in cancerous cells by USP17, a cytokine-inducible DUB encoding two hyaluronan binding motifs (HABMs) showing direct interaction with hyaluronan (HA), could prove a promising step in the development of DUBs containing HABMs as agents in anticancer therapeutics. In this review, we summarize the importance of hyaluronan (HA) in cancer, the role played by DUBs in apoptosis, and a possible relationship between DUBs and HA in cancerous cells, suggesting new strategies for applying DUB enzymes as potential anticancer therapeutics.
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Affiliation(s)
- Suresh Ramakrishna
- Department of Biomedical Science, CHA University, Bundang CHA Hospital, Gyeonggi-Do 463-400, Republic of Korea
| | - Bharathi Suresh
- Department of Biomedical Science, CHA University, Bundang CHA Hospital, Gyeonggi-Do 463-400, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA University, Bundang CHA Hospital, Gyeonggi-Do 463-400, Republic of Korea.
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50
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Ohayon S, Refua M, Hendler A, Aharoni A, Brik A. Harnessing the Oxidation Susceptibility of Deubiquitinases for Inhibition with Small Molecules. Angew Chem Int Ed Engl 2014. [DOI: 10.1002/ange.201408411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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