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Wu YC, Su BH, Cheng WH, Zou CT, Yeh ETH, Yang FM. CYLD links the TRAF6/sNASP axis to TLR4 signaling in sepsis-induced acute lung injury. Cell Mol Life Sci 2025; 82:124. [PMID: 40108019 PMCID: PMC11923351 DOI: 10.1007/s00018-025-05654-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 03/03/2025] [Accepted: 03/09/2025] [Indexed: 03/22/2025]
Abstract
Sepsis-induced acute lung injury (ALI) involves severe lung dysfunction and leads to high morbidity and mortality rates due to the lack of effective treatments. The somatic nuclear autoantigenic sperm protein (sNASP)/tumor necrosis factor receptor-associated factor 6 (TRAF6) axis plays a crucial role in regulating inflammatory responses during sepsis through Toll-like receptor 4 (TLR4) signaling. However, it is unclear whether deubiquitinating enzymes affect the TRAF6/sNASP axis. In this study, we showed that cylindromatosis (CYLD) directly binds to the sNASP and prevents TRAF6 activation. When TLR4 is activated, phosphorylation of sNASP releases CYLD from the TRAF6/sNASP complex, leading to TRAF6 autoubiquitination and the production of proinflammatory cytokines. To stop TRAF6 activation, a complex of sNASP, TRAF6, and CYLD is reformed once dephosphorylation of sNASP occurs by protein phosphatase 4 (PP4). Silencing sNASP negated the inhibitory effects of CYLD on interleukin (IL)-6 and TNF-α production after lipopolysaccharide (LPS) treatment. Similarly, the absence of CYLD also reduced PP4's negatively regulated production of proinflammatory cytokines, indicating that phosphorylation is crucial for the interaction between sNASP and CYLD as well as TRAF6 activation. Finally, mice infected with a recombinant adenovirus carrying the CYLD gene (Ad-CYLD WT), but not a mutation, showed significant reductions in cecal ligation and puncture (CLP)-mediated lung injury and proinflammatory cytokine production. In conclusion, CYLD alleviated sepsis-induced inflammation by interacting with the TRAF6/sNASP axis. These findings suggest that CYLD could be a potential therapeutic target for treating sepsis-induced ALI.
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Affiliation(s)
- Yu-Chih Wu
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Bing-Hua Su
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Wun-Hao Cheng
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Cheng-Tai Zou
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Edward T H Yeh
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Feng-Ming Yang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
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Chen Y, Dai R, Cheng M, Wang W, Liu C, Cao Z, Ge Y, Wang Y, Zhang L. Status and role of the ubiquitin-proteasome system in renal fibrosis. Biomed Pharmacother 2024; 178:117210. [PMID: 39059348 DOI: 10.1016/j.biopha.2024.117210] [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: 05/11/2024] [Revised: 07/23/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024] Open
Abstract
The ubiquitin-proteasome system (UPS) is a basic regulatory mechanism in cells that is essential for maintaining cell homeostasis, stimulating signal transduction, and determining cell fate. These biological processes require coordinated signaling cascades across members of the UPS to achieve substrate ubiquitination and deubiquitination. The role of the UPS in fibrotic diseases has attracted widespread attention, and the aberrant expression of UPS members affects the fibrosis process. In this review, we provide an overview of the UPS and its relevance for fibrotic diseases. Moreover, for the first time, we explore in detail how the UPS promotes or inhibits renal fibrosis by regulating biological processes such as signaling pathways, inflammation, oxidative stress, and the cell cycle, emphasizing the status and role of the UPS in renal fibrosis. Further research on this system may reveal new strategies for preventing renal fibrosis.
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Affiliation(s)
- Yizhen Chen
- First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, China
| | - Rong Dai
- Department of Nephrology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Meng Cheng
- Department of Nephrology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Weili Wang
- First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, China
| | - Chuanjiao Liu
- First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, China
| | - Zeping Cao
- First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, China
| | - Yong Ge
- First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, China
| | - Yiping Wang
- Department of Nephrology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
| | - Lei Zhang
- Department of Nephrology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
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Rinotas V, Iliaki K, Pavlidi L, Meletakos T, Mosialos G, Armaka M. Cyld restrains the hyperactivation of synovial fibroblasts in inflammatory arthritis by regulating the TAK1/IKK2 signaling axis. Cell Death Dis 2024; 15:584. [PMID: 39122678 PMCID: PMC11316070 DOI: 10.1038/s41419-024-06966-2] [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: 02/07/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024]
Abstract
TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Herein, we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NF-κB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.
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Affiliation(s)
- Vagelis Rinotas
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center (BSRC) "Alexander Fleming", Vari, Greece
| | - Kalliopi Iliaki
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center (BSRC) "Alexander Fleming", Vari, Greece
| | - Lydia Pavlidi
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center (BSRC) "Alexander Fleming", Vari, Greece
| | - Theodore Meletakos
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center (BSRC) "Alexander Fleming", Vari, Greece
| | - George Mosialos
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Marietta Armaka
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center (BSRC) "Alexander Fleming", Vari, Greece.
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4
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Ni H, Chen M, Dong D, Zhou Y, Cao Y, Ge R, Luo X, Wang Y, Dong X, Zhou J, Li D, Xie S, Liu M. CYLD/HDAC6 signaling regulates the interplay between epithelial-mesenchymal transition and ciliary homeostasis during pulmonary fibrosis. Cell Death Dis 2024; 15:581. [PMID: 39122680 PMCID: PMC11316090 DOI: 10.1038/s41419-024-06972-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
The primary cilium behaves as a platform for sensing and integrating extracellular cues to control a plethora of cellular activities. However, the functional interaction of this sensory organelle with epithelial-mesenchymal transition (EMT) during pulmonary fibrosis remains unclear. Here, we reveal a critical role for cylindromatosis (CYLD) in reciprocally linking the EMT program and ciliary homeostasis during pulmonary fibrosis. A close correlation between the EMT program and primary cilia is observed in bleomycin-induced pulmonary fibrosis as well as TGF-β-induced EMT model. Mechanistic study reveals that downregulation of CYLD underlies the crosstalk between EMT and ciliary homeostasis by inactivating histone deacetylase 6 (HDAC6) during pulmonary fibrosis. Moreover, manipulation of primary cilia is an effective means to modulate the EMT program. Collectively, these results identify a pivotal role for the CYLD/HDAC6 signaling in regulating the reciprocal interplay between the EMT program and ciliary homeostasis during pulmonary fibrosis.
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Affiliation(s)
- Hua Ni
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China
- Key Laboratory of Biological Resources and Ecology of Pamirs Plateau in Xinjiang Uygur Autonomous Region, College of Life and Geographic Sciences, Kashi University, Kashi, China
| | - Miao Chen
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Dan Dong
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China
| | - Yunqiang Zhou
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China
| | - Yu Cao
- Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Ruixin Ge
- Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Xiangrui Luo
- Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Yutao Wang
- Key Laboratory of Biological Resources and Ecology of Pamirs Plateau in Xinjiang Uygur Autonomous Region, College of Life and Geographic Sciences, Kashi University, Kashi, China
| | - Xifeng Dong
- Department of Hematology, Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin Institute of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jun Zhou
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China
- Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Dengwen Li
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
| | - Songbo Xie
- Department of Ophthalmology, Tianjin Medical University General Hospital, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, Haihe Laboratory of Cell Ecosystem, Tianjin Medical University, Tianjin, 300052, China.
| | - Min Liu
- Laboratory of Tissue Homeostasis, Haihe Laboratory of Cell Ecosystem, Tianjin, China.
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Tang H, Gupta A, Morrisroe SA, Bao C, Schwantes-An TH, Gupta G, Liang S, Sun Y, Chu A, Luo A, Elangovan VR, Sangam S, Shi Y, Naidu SR, Jheng JR, Ciftci-Yilmaz S, Warfel NA, Hecker L, Mitra S, Coleman AW, Lutz KA, Pauciulo MW, Lai YC, Javaheri A, Dharmakumar R, Wu WH, Flaherty DP, Karnes JH, Breuils-Bonnet S, Boucherat O, Bonnet S, Yuan JXJ, Jacobson JR, Duarte JD, Nichols WC, Garcia JGN, Desai AA. Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension. Circulation 2024; 150:302-316. [PMID: 38695173 PMCID: PMC11262989 DOI: 10.1161/circulationaha.123.065304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 03/04/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.
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Affiliation(s)
- Haiyang Tang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Akash Gupta
- Department of Medicine and Arizona Health Sciences Center, Department of Cellular and Molecular Medicine, College of Medicine-Tucson, University of Arizona, Tucson, AZ
| | - Seth A. Morrisroe
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
| | - Changlei Bao
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- College of Veterinary Medicine, Northwest A & F University, Yangling, China
| | - Tae-Hwi Schwantes-An
- Department of Medical & Molecular Genetics, Indiana University, Indianapolis, IN
| | - Geetanjali Gupta
- Department of Medicine and Arizona Health Sciences Center, Department of Cellular and Molecular Medicine, College of Medicine-Tucson, University of Arizona, Tucson, AZ
| | - Shuxin Liang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yanan Sun
- College of Veterinary Medicine, Northwest A & F University, Yangling, China
| | - Aiai Chu
- Department of Echocardiography, Gansu Provincial Hospital, Lanzhou, China
| | - Ang Luo
- College of Veterinary Medicine, Northwest A & F University, Yangling, China
- Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | | | - Shreya Sangam
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
| | - Yinan Shi
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
- College of Veterinary Medicine, Northwest A & F University, Yangling, China
| | - Samisubbu R. Naidu
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
| | - Jia-Rong Jheng
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN
| | - Sultan Ciftci-Yilmaz
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
| | - Noel A. Warfel
- Department of Medicine and Arizona Health Sciences Center, Department of Cellular and Molecular Medicine, College of Medicine-Tucson, University of Arizona, Tucson, AZ
| | - Louise Hecker
- Department of Medicine, Emory University, and Atlanta VA Healthcare System, Atlanta, GA
| | - Sumegha Mitra
- Department of Obstetrics & Gynecology, Indiana University, Indianapolis, IN
| | - Anna W. Coleman
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Katie A. Lutz
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Michael W. Pauciulo
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Yen-Chun Lai
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN
| | - Ali Javaheri
- Department of Medicine, Washington University and John Cochran VA Hospital, St. Louis, MO
| | - Rohan Dharmakumar
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
| | - Wen-Hui Wu
- Department of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, CA
| | - Daniel P Flaherty
- Department of Medicinal Chemistry and Molecular Pharmcacology, Purdue University, Lafayette, IN
| | - Jason H Karnes
- Department of Pharmacy Practice and Science, R Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ
| | - Sandra Breuils-Bonnet
- Department of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, CA
| | - Olivier Boucherat
- Department of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, CA
| | - Sebastien Bonnet
- Department of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, CA
| | - Jason X-J Yuan
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | | | - Julio D Duarte
- Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL
| | - William C Nichols
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Joe GN Garcia
- The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL
| | - Ankit A. Desai
- Krannert Cardiovascular Research Center, Department of Medicine, Indiana University, Indianapolis, IN
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Chen R, Zhang H, Li L, Li J, Xie J, Weng J, Tan H, Liu Y, Guo T, Wang M. Roles of ubiquitin-specific proteases in inflammatory diseases. Front Immunol 2024; 15:1258740. [PMID: 38322269 PMCID: PMC10844489 DOI: 10.3389/fimmu.2024.1258740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/02/2024] [Indexed: 02/08/2024] Open
Abstract
Ubiquitin-specific proteases (USPs), as one of the deubiquitinating enzymes (DUBs) families, regulate the fate of proteins and signaling pathway transduction by removing ubiquitin chains from the target proteins. USPs are essential for the modulation of a variety of physiological processes, such as DNA repair, cell metabolism and differentiation, epigenetic modulations as well as protein stability. Recently, extensive research has demonstrated that USPs exert a significant impact on innate and adaptive immune reactions, metabolic syndromes, inflammatory disorders, and infection via post-translational modification processes. This review summarizes the important roles of the USPs in the onset and progression of inflammatory diseases, including periodontitis, pneumonia, atherosclerosis, inflammatory bowel disease, sepsis, hepatitis, diabetes, and obesity. Moreover, we highlight a comprehensive overview of the pathogenesis of USPs in these inflammatory diseases as well as post-translational modifications in the inflammatory responses and pave the way for future prospect of targeted therapies in these inflammatory diseases.
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Affiliation(s)
- Rui Chen
- Center of Obesity and Metabolic Diseases, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- Department of Stomatology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Hui Zhang
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
- College of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Linke Li
- Center of Obesity and Metabolic Diseases, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- Department of Stomatology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Jinsheng Li
- College of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Jiang Xie
- Department of Pediatrics, Chengdu Third People's Hospital, Chengdu, Sichuan, China
| | - Jie Weng
- College of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Huan Tan
- Center of Obesity and Metabolic Diseases, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Yanjun Liu
- Center of Obesity and Metabolic Diseases, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Tailin Guo
- Center of Obesity and Metabolic Diseases, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Mengyuan Wang
- Center of Obesity and Metabolic Diseases, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- Department of Stomatology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
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7
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Su C, Zhang H, Mo J, Liao Z, Zhang B, Zhu P. SP1-activated USP27X-AS1 promotes hepatocellular carcinoma progression via USP7-mediated AKT stabilisation. Clin Transl Med 2024; 14:e1563. [PMID: 38279869 PMCID: PMC10819096 DOI: 10.1002/ctm2.1563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/11/2023] [Accepted: 01/14/2024] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) continues to pose a significant threat to patient survival. Emerging evidence underscores the pivotal involvement of long non-coding RNAs (lncRNAs) in the cancer process. Nevertheless, our understanding of the roles and processes of lncRNAs in HCC remains limited. METHODS The expression level of USP27X-AS1 was assessed in an HCC patient cohort through a combination of bioinformatics analysis and qRT-PCR. Subsequent biological experiments were conducted to delve into the functional aspects of USP27X-AS1. Additional molecular biology techniques, including RNA pulldown and RNA immunoprecipitation (RIP), were employed to elucidate the potential mechanisms involving USP27X-AS1 in HCC. Finally, CUT-RUN assay and other investigations were carried out to determine the factors contributing to the heightened expression of USP27X-AS1 in HCC. RESULTS High expression of the novel oncogene USP27X-AS1 predicted poor prognosis in HCC patients. Further investigation confirmed that USP27X-AS1 promoted the proliferation and metastasis of HCC by enabling USP7 to interact with AKT, which reduced level of AKT poly-ubiquitylation and enhanced AKT protein stability, which improves protein stabilisation of AKT and promotes the progression of HCC. Moreover, we also revealed that SP1 binds to USP27X-AS1 promoter to activate its transcription. CONCLUSIONS Novel oncogenic lncRNA USP27X-AS1 promoted HCC progression via recruiting USP7 to deubiquitinate AKT. SP1 transcriptionally activated USP27X-AS1 expression. These findings shed light on HCC and pointed to USP27X-AS1 as a potential predictive biomarker and treatment target for the malignancy.
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Affiliation(s)
- Chen Su
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiPeople's Republic of China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubeiPeople's Republic of China
| | - Haoquan Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiPeople's Republic of China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubeiPeople's Republic of China
| | - Jie Mo
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiPeople's Republic of China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubeiPeople's Republic of China
| | - Zhibin Liao
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiPeople's Republic of China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubeiPeople's Republic of China
| | - Bixiang Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiPeople's Republic of China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubeiPeople's Republic of China
- Key Laboratory of Organ TransplantationMinistry of EducationWuhanHubeiPeople's Republic of China
- Key Laboratory of Organ TransplantationNational Health CommissionWuhanHubeiPeople's Republic of China
- Key Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhanHubeiPeople's Republic of China
| | - Peng Zhu
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiPeople's Republic of China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubeiPeople's Republic of China
- Key Laboratory of Organ TransplantationMinistry of EducationWuhanHubeiPeople's Republic of China
- Key Laboratory of Organ TransplantationNational Health CommissionWuhanHubeiPeople's Republic of China
- Key Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhanHubeiPeople's Republic of China
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8
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Bekas N, Samiotaki M, Papathanasiou M, Mokos P, Pseftogas A, Xanthopoulos K, Thanos D, Mosialos G, Dafou D. Inactivation of Tumor Suppressor CYLD Inhibits Fibroblast Reprogramming to Pluripotency. Cancers (Basel) 2023; 15:4997. [PMID: 37894364 PMCID: PMC10605754 DOI: 10.3390/cancers15204997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
CYLD is a tumor suppressor gene coding for a deubiquitinating enzyme that has a critical regulatory function in a variety of signaling pathways and biological processes involved in cancer development and progression, many of which are also key modulators of somatic cell reprogramming. Nevertheless, the potential role of CYLD in this process has not been studied. With the dual aim of investigating the involvement of CYLD in reprogramming and developing a better understanding of the intricate regulatory system governing this process, we reprogrammed control (CYLDWT/WT) and CYLD DUB-deficient (CYLDΔ9/Δ9) mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs) through ectopic overexpression of the Yamanaka factors (Oct3/4, Sox2, Klf4, c-myc). CYLD DUB deficiency led to significantly reduced reprogramming efficiency and slower early reprogramming kinetics. The introduction of WT CYLD to CYLDΔ9/Δ9 MEFs rescued the phenotype. Nevertheless, CYLD DUB-deficient cells were capable of establishing induced pluripotent colonies with full spontaneous differentiation potential of the three germ layers. Whole proteome analysis (Data are available via ProteomeXchange with identifier PXD044220) revealed that the mesenchymal-to-epithelial transition (MET) during the early reprogramming stages was disrupted in CYLDΔ9/Δ9 MEFs. Interestingly, differentially enriched pathways revealed that the primary processes affected by CYLD DUB deficiency were associated with the organization of the extracellular matrix and several metabolic pathways. Our findings not only establish for the first time CYLD's significance as a regulatory component of early reprogramming but also highlight its role as an extracellular matrix regulator, which has profound implications in cancer research.
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Affiliation(s)
- Nikolaos Bekas
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.B.); (P.M.); (G.M.)
| | - Martina Samiotaki
- Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Greece;
| | - Maria Papathanasiou
- Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece; (M.P.); (D.T.)
| | - Panagiotis Mokos
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.B.); (P.M.); (G.M.)
| | - Athanasios Pseftogas
- Division of Experimental Oncology, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Konstantinos Xanthopoulos
- Laboratory of Pharmacology, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Dimitris Thanos
- Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece; (M.P.); (D.T.)
| | - George Mosialos
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.B.); (P.M.); (G.M.)
| | - Dimitra Dafou
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.B.); (P.M.); (G.M.)
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9
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Zhang S, Guo Y, Zhang S, Wang Z, Zhang Y, Zuo S. Targeting the deubiquitinase USP2 for malignant tumor therapy (Review). Oncol Rep 2023; 50:176. [PMID: 37594087 PMCID: PMC10463009 DOI: 10.3892/or.2023.8613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/24/2023] [Indexed: 08/19/2023] Open
Abstract
The ubiquitin‑proteasome system is a major degradation pathway for >80% of proteins in vivo. Deubiquitylases, which remove ubiquitinated tags to stabilize substrate proteins, are important components involved in regulating the degradation of ubiquitinated proteins. In addition, they serve multiple roles in tumor development by participating in physiological processes such as protein metabolism, cell cycle regulation, DNA damage repair and gene transcription. The present review systematically summarized the role of ubiquitin‑specific protease 2 (USP2) in malignant tumors and the specific molecular mechanisms underlying the involvement of USP2 in tumor‑associated pathways. USP2 reverses ubiquitin‑mediated degradation of proteins and is involved in aberrant proliferation, migration, invasion, apoptosis and drug resistance of tumors. Additionally, the present review summarized studies reporting on the use of USP2 as a therapeutic target for malignancies such as breast, liver, ovarian, colorectal, bladder and prostate cancers and glioblastoma and highlights the current status of pharmacological research on USP2. The clinical significance of USP2 as a therapeutic target for malignant tumors warrants further investigation.
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Affiliation(s)
- Shilong Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Yi Guo
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Shenjie Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Zhi Wang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Yewei Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- Precision Medicine Research Institute of Guizhou, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
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10
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Paccosi E, Balzerano A, Proietti-De-Santis L. Interfering with the Ubiquitin-Mediated Regulation of Akt as a Strategy for Cancer Treatment. Int J Mol Sci 2023; 24:ijms24032809. [PMID: 36769122 PMCID: PMC9917864 DOI: 10.3390/ijms24032809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/26/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
The serine/threonine kinase Akt modulates the functions of numerous substrates, many of them being involved in cell proliferation and growth, metabolism, angiogenesis, resistance to hypoxia and migration. Akt is frequently deregulated in many types of human cancers, its overexpression or abnormal activation being associated with the increased proliferation and survival of cancer cells. A promising avenue for turning off the functionality of Akt is to either interfere with the K63-linked ubiquitination that is necessary for Akt membrane recruitment and activation or increase the K48-linked polyubiquitination that aims to target Akt to the proteasome for its degradation. Recent evidence indicates that targeting the ubiquitin proteasome system is effective for certain cancer treatments. In this review, the functions and roles of Akt in human cancer will be discussed, with a main focus on molecules and compounds that target various elements of the ubiquitination processes that regulate the activation and inactivation of Akt. Moreover, their possible and attractive implications for cancer therapy will be discussed.
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11
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Zhang X, Zhang Y, Zhou P, Ai J, Liu X, Zhang Q, Wang Z, Wang H, Zhang W, Zhang J, Huang Y. Down-regulated cylindromatosis enhances NF-κB activation and aggravates inflammation in HBV-ACLF patients. Emerg Microbes Infect 2022; 11:1586-1601. [PMID: 35579924 PMCID: PMC9186363 DOI: 10.1080/22221751.2022.2077128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The pathogenesis of liver in patients with hepatitis B virus-associated acute chronic liver failure (HBV-ACLF) remains largely unknown. We aimed to elucidate the molecular mechanism underlying the pathogenesis of liver in HBV-ACLF patients by using multiple approaches including transcriptome analysis. We performed transcriptomic sequencing analysis on the liver of HBV-ACLF patients (n = 6), chronic hepatitis B (n = 6), liver cirrhosis (n = 6) and normal control (n = 5), then explored the potential pathogenesis mechanism in liver specimen from another 48 subjects and further validated the molecular and cellular mechanisms using THP-1 cells. RNA-sequencing data analysis indicated that, among the genes up-regulated in HBV-ACLF, genes related to inflammatory response and chemotaxis accounted for a large proportion of the total DEGs. A number of key chemokines (CCL2, CCL5, CCL20, CXCL5, CXCL6, CXCL8) and NF-ĸB pathway were identified to be robust in the liver samples from HBV-ACLF patients. Interestingly, cylindromatosis (CYLD) was found to be downregulated in the liver of HBV-ACLF patients, in line with the well-established role of CYLD in regulating most of the chemokines and pro-inflammatory cytokines (CCL2, CCL5, CCL20, CXCL5, CXCL6, CXCL8, IL-6, IL-1β) via inhibition of NF-ĸB. Indeed, the knockdown of CYLD resulted in sustained activation of NF-ĸB in macrophages and enhanced chemokines and inflammatory cytokines production, which in turn enhanced chemotactic migration of neutrophil, monocyte, T lymphocytes, and NK cell. In conclusions, down-regulated CYLD aggravated inflammatory cell chemotaxis through enhancing NF-κB activation in HBV-ACLF patients, thereby participating in the pathogenesis of HBV-ACLF injury.
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Affiliation(s)
- Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Pu Zhou
- Huashan Worldwide Medical Center, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jingwen Ai
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xiaoqin Liu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Quanbao Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hongyan Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Wenhong Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.,Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.,Department of Infectious Diseases Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yuxian Huang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People's Republic of China
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12
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Gonzalez-Santamarta M, Bouvier C, Rodriguez MS, Xolalpa W. Ubiquitin-chains dynamics and its role regulating crucial cellular processes. Semin Cell Dev Biol 2022; 132:155-170. [PMID: 34895814 DOI: 10.1016/j.semcdb.2021.11.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022]
Abstract
The proteome adapts to multiple situations occurring along the life of the cell. To face these continuous changes, the cell uses posttranslational modifications (PTMs) to control the localization, association with multiple partners, stability, and activity of protein targets. One of the most dynamic protein involved in PTMs is Ubiquitin (Ub). Together with other members of the same family, known as Ubiquitin-like (UbL) proteins, Ub rebuilds the architecture of a protein in a few minutes to change its properties in a very efficient way. This capacity of Ub and UbL is in part due to their potential to form complex architectures when attached to target proteins or when forming Ub chains. The highly dynamic formation and remodeling of Ub chains is regulated by the action of conjugating and deconjugating enzymes that determine, in due time, the correct chain architecture for a particular cellular function. Chain remodeling occurs in response to physiologic stimuli but also in pathologic situations. Here, we illustrate well-documented cases of chain remodeling during DNA repair, activation of the NF-κB pathway and autophagy, as examples of this dynamic regulation. The crucial role of enzymes and cofactors regulating chain remodeling is discussed.
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Affiliation(s)
- Maria Gonzalez-Santamarta
- Laboratoire de Chimie de Coordination (LCC) - UPR 8241 CNRS, and UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31400 Toulouse, France.
| | - Corentin Bouvier
- Laboratoire de Chimie de Coordination (LCC) - UPR 8241 CNRS, and UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31400 Toulouse, France.
| | - Manuel S Rodriguez
- Laboratoire de Chimie de Coordination (LCC) - UPR 8241 CNRS, and UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31400 Toulouse, France.
| | - Wendy Xolalpa
- Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, Universidad Nacional Autónoma de México, 62250 Cuernavaca, Morelos, Mexico.
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13
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Kanemaru A, Shinriki S, Kai M, Tsurekawa K, Ozeki K, Uchino S, Suenaga N, Yonemaru K, Miyake S, Masuda T, Kariya R, Okada S, Takeshita H, Seki Y, Yano H, Komohara Y, Yoshida R, Nakayama H, Li JD, Saito H, Jono H. Potential use of EGFR-targeted molecular therapies for tumor suppressor CYLD-negative and poor prognosis oral squamous cell carcinoma with chemoresistance. Cancer Cell Int 2022; 22:358. [PMID: 36376983 PMCID: PMC9664721 DOI: 10.1186/s12935-022-02781-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/04/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Tumor suppressor CYLD dysfunction by loss of its expression, triggers malignant transformation, especially drug resistance and tumor invasion/metastasis. Although loss of CYLD expression is significantly associated with poor prognosis in a large variety of tumors, no clinically-effective treatment for CYLD-negative cancer patients is available. METHODS We focused on oral squamous cell carcinoma (OSCC), and sought to develop novel therapeutic agents for CYLD-negative cancer patients with poor prognosis. CYLD-knockdown OSCC cells by using CYLD-specific siRNA, were used to elucidate and determine the efficacy of novel drug candidates by evaluating cell viability and epithelial-mesenchymal transition (EMT)-like change. Therapeutic effects of candidate drug on cell line-derived xenograft (CDX) model and usefulness of CYLD as a novel biomarker using patient-derived xenograft (PDX) model were further investigated. RESULTS CYLD-knockdown OSCC cells were resistant for all currently-available cytotoxic chemotherapeutic agents for OSCC, such as, cisplatin, 5-FU, carboplatin, docetaxel, and paclitaxel. By using comprehensive proteome analysis approach, we identified epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, played key roles in CYLD-knockdown OSCC cells. Indeed, cell survival rate in the cisplatin-resistant CYLD-knockdown OSCC cells was markedly inhibited by treatment with clinically available EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib. In addition, gefitinib was significantly effective for not only cell survival, but also EMT-like changes through inhibiting transforming growth factor-β (TGF-β) signaling in CYLD-knockdown OSCC cells. Thereby, overall survival of CYLD-knockdown CDX models was significantly prolonged by gefitinib treatment. Moreover, we found that CYLD expression was significantly associated with gefitinib response by using PDX models. CONCLUSIONS Our results first revealed that EGFR-targeted molecular therapies, such as EGFR-TKIs, could have potential to be novel therapeutic agents for the CYLD-negative OSCC patients with poor prognosis.
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Affiliation(s)
- Ayumi Kanemaru
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Satoru Shinriki
- Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Mimi Kai
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Kanae Tsurekawa
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Kazuya Ozeki
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Shota Uchino
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Naoki Suenaga
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Kou Yonemaru
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
| | - Shunsuke Miyake
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
- Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Takeshi Masuda
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe honmachi, Chuo-Ku, Kumamoto, 862-0973, Japan
| | - Ryusho Kariya
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Hisashi Takeshita
- Department of Oral & Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Yuki Seki
- Department of Oral & Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Hiromu Yano
- Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Ryoji Yoshida
- Department of Oral & Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Hideki Nakayama
- Department of Oral & Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Jian-Dong Li
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Hideyuki Saito
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
- Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Hirofumi Jono
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan.
- Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan.
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Tsai PJ, Lai YH, Manne RK, Tsai YS, Sarbassov D, Lin HK. Akt: a key transducer in cancer. J Biomed Sci 2022; 29:76. [PMID: 36180910 PMCID: PMC9526305 DOI: 10.1186/s12929-022-00860-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/21/2022] [Indexed: 01/27/2023] Open
Abstract
Growth factor signaling plays a pivotal role in diverse biological functions, such as cell growth, apoptosis, senescence, and migration and its deregulation has been linked to various human diseases. Akt kinase is a central player transmitting extracellular clues to various cellular compartments, in turn executing these biological processes. Since the discovery of Akt three decades ago, the tremendous progress towards identifying its upstream regulators and downstream effectors and its roles in cancer has been made, offering novel paradigms and therapeutic strategies for targeting human diseases and cancers with deregulated Akt activation. Unraveling the molecular mechanisms for Akt signaling networks paves the way for developing selective inhibitors targeting Akt and its signaling regulation for the management of human diseases including cancer.
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Affiliation(s)
- Pei-Jane Tsai
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Hsin Lai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Rajesh Kumar Manne
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yau-Sheng Tsai
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Dos Sarbassov
- Biology Department, School of Sciences and Humanities, and National Laboratory Astana, Nazarbayev University, Nur-Sultan City, 010000, Kazakhstan.
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
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15
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Zajicek AS, Ruan H, Dai H, Skolfield MC, Phillips HL, Burnette WJ, Javidfar B, Sun SC, Akbarian S, Yao WD. Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling. Mol Psychiatry 2022; 27:2414-2424. [PMID: 35449295 PMCID: PMC9278694 DOI: 10.1038/s41380-022-01571-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/04/2022] [Accepted: 04/07/2022] [Indexed: 11/09/2022]
Abstract
The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.
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Affiliation(s)
- Alexis S Zajicek
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
- Neuroscience Graduate Program, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
| | - Hongyu Ruan
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
| | - Huihui Dai
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
| | - Mary C Skolfield
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
- Neuroscience Graduate Program, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
| | - Hannah L Phillips
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
- Neuroscience Graduate Program, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
| | - Wendi J Burnette
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
- Neuroscience Graduate Program, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
| | - Behnam Javidfar
- Friedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Shao-Cong Sun
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Schahram Akbarian
- Friedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Wei-Dong Yao
- Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
- Neuroscience Graduate Program, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
- Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
- Harvard Medical School, New England Primate Research Center, Southborough, MA, USA.
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA.
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16
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Chen R, Pang X, Li L, Zeng Z, Chen M, Zhang S. Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation. Cell Death Dis 2022; 13:139. [PMID: 35145062 PMCID: PMC8831562 DOI: 10.1038/s41419-022-04566-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/06/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023]
Abstract
The exact pathogenesis of inflammatory bowel disease (IBD), a chronic gastrointestinal inflammatory disease comprising Crohn’s disease and ulcerative colitis, remains unclear. Studies on ubiquitination, which regulates the degradation of inflammation signalling pathway molecules, and deubiquitination have provided novel insights. Targeting the ubiquitin-specific protease (USP) family of deubiquitinases elucidates IBD signalling pathway mechanisms and possibly, IBD therapeutic solutions. Here, we characterised USPs as chief regulators of pro-inflammatory signalling pathways, including nuclear factor-κB and transforming growth factor-β; analysed the relationship between USPs and IBD pathogenesis in terms of genetic susceptibility, intestinal epithelial barrier, immunity, and gut microbiota; and discussed future research prospects.
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Affiliation(s)
- Rirong Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaobai Pang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Li Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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17
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Nagy N, Dubois A, Szell M, Rajan N. Genetic Testing in CYLD Cutaneous Syndrome: An Update. APPLICATION OF CLINICAL GENETICS 2021; 14:427-444. [PMID: 34744449 PMCID: PMC8566010 DOI: 10.2147/tacg.s288274] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 10/05/2021] [Indexed: 01/03/2023]
Abstract
CYLD cutaneous syndrome (CCS) is an inclusive label for the inherited skin adnexal tumour syndromes Brooke–Spiegler Syndrome (BSS-OMIM 605041), familial cylindromatosis (FC – OMIM 132700) and multiple familial trichoepitheliomas (MFT-OMIM 601606). All three syndromes arise due to germline pathogenic variants in CYLD, a tumour suppressor gene (OMIM 605018). CCS is transmitted in an autosomal dominant pattern, and has variable expressivity, both of the three syndromic phenotypes, and of the severity of tumour burden. Age-related penetrance figures are not precisely reported. The first tumours typically appear during puberty and progressively accumulate through adulthood. Penetrance is typically high, with equal numbers of males and females affected. Genetic testing is important for confirmation of the clinical diagnosis, genetic counselling and family planning, including preimplantation diagnosis. Additionally, identified CCS patients may be eligible for future clinical trials of non-surgical pre-emptive interventions that aim to prevent tumour growth. In this update, we review the clinical presentations of germline and mosaic CCS. An overview of the germline pathogenic variant spectrum of patients with CCS reveals more than 100 single nucleotide variants and small insertions and deletions in coding exons, most frequently resulting in predicted truncation. In addition, a minority of patients have large deletions involving the CYLD gene, intronic pathogenic variants that affect splicing, or inversions. We discuss germline and somatic testing approaches. Somatic testing of tumour tissue, relevant in mosaic CCS, can reveal recurrently detected pathogenic variants when two or more tumours are tested. This can influence genetic testing of children, who may inherit this as a germline variant, and inform genetic counselling and prenatal diagnosis. Finally, we discuss testing technologies that are currently used, their benefits and limitations, and future directions for genetic testing in CCS.
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Affiliation(s)
- Nikoletta Nagy
- Department of Medical Genetics, University of Szeged, Szeged, Hungary.,Dermatological Research Group of the Eotvos Lorand Research Network, University of Szeged, Szeged, Hungary
| | - Anna Dubois
- Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
| | - Marta Szell
- Department of Medical Genetics, University of Szeged, Szeged, Hungary.,Dermatological Research Group of the Eotvos Lorand Research Network, University of Szeged, Szeged, Hungary
| | - Neil Rajan
- Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.,Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK
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18
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Wozniak M, Czyz M. The Functional Role of Long Non-Coding RNAs in Melanoma. Cancers (Basel) 2021; 13:cancers13194848. [PMID: 34638331 PMCID: PMC8508152 DOI: 10.3390/cancers13194848] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/23/2021] [Accepted: 09/25/2021] [Indexed: 12/15/2022] Open
Abstract
Melanoma is the most lethal skin cancer, with increasing incidence worldwide. The molecular events that drive melanoma development and progression have been extensively studied, resulting in significant improvements in diagnostics and therapeutic approaches. However, a high drug resistance to targeted therapies and adverse effects of immunotherapies are still a major challenge in melanoma treatment. Therefore, the elucidation of molecular mechanisms of melanomagenesis and cancer response to treatment is of great importance. Recently, many studies have revealed the close association of long noncoding RNAs (lncRNAs) with the development of many cancers, including melanoma. These RNA molecules are able to regulate a plethora of crucial cellular processes including proliferation, differentiation, migration, invasion and apoptosis through diverse mechanisms, and even slight dysregulation of their expression may lead to tumorigenesis. lncRNAs are able to bind to protein complexes, DNA and RNAs, affecting their stability, activity, and localization. They can also regulate gene expression in the nucleus. Several functions of lncRNAs are context-dependent. This review summarizes current knowledge regarding the involvement of lncRNAs in melanoma. Their possible role as prognostic markers of melanoma response to treatment and in resistance to therapy is also discussed.
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19
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Barnabei L, Laplantine E, Mbongo W, Rieux-Laucat F, Weil R. NF-κB: At the Borders of Autoimmunity and Inflammation. Front Immunol 2021; 12:716469. [PMID: 34434197 PMCID: PMC8381650 DOI: 10.3389/fimmu.2021.716469] [Citation(s) in RCA: 333] [Impact Index Per Article: 83.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/22/2021] [Indexed: 12/18/2022] Open
Abstract
The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory response. In the first part of this review, we discuss the NF-κB inducers, signaling pathways, and regulators involved in immune homeostasis as well as detail the importance of post-translational regulation by ubiquitination in NF-κB function. We also indicate the stages of central and peripheral tolerance where NF-κB plays a fundamental role. With respect to central tolerance, we detail how NF-κB regulates medullary thymic epithelial cell (mTEC) development, homeostasis, and function. Moreover, we elaborate on its role in the migration of double-positive (DP) thymocytes from the thymic cortex to the medulla. With respect to peripheral tolerance, we outline how NF-κB contributes to the inactivation and destruction of autoreactive T and B lymphocytes as well as the differentiation of CD4+-T cell subsets that are implicated in immune tolerance. In the latter half of the review, we describe the contribution of NF-κB to the pathogenesis of autoimmunity and autoinflammation. The recent discovery of mutations involving components of the pathway has both deepened our understanding of autoimmune disease and informed new therapeutic approaches to treat these illnesses.
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Affiliation(s)
- Laura Barnabei
- INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute Paris Descartes Sorbonne Paris Cité University, Paris, France
| | - Emmanuel Laplantine
- Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France
| | - William Mbongo
- Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France
| | - Frédéric Rieux-Laucat
- INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute Paris Descartes Sorbonne Paris Cité University, Paris, France
| | - Robert Weil
- Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France
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20
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Li T, Wang Y, Li D, Zhou J, Zhang B, He X. Potential role for the tumor suppressor CYLD in brain and notochord development. Thorac Cancer 2021; 12:1900-1908. [PMID: 33982884 PMCID: PMC8201528 DOI: 10.1111/1759-7714.13973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/08/2021] [Accepted: 04/11/2021] [Indexed: 12/12/2022] Open
Abstract
Background The cylindromatosis (CYLD) tumor suppressor is a microtubule‐associated deubiquitinase that plays a critical role in the regulation of cell signaling and contributes to a variety of physiological and pathological processes. However, the functions of CYLD in zebrafish are less well known, particularly with regard to their development and physiology. In this context, we investigated the loss of function of CYLD in zebrafish via transcription activator‐like effector nuclease (TALEN)‐based gene deletion. Methods Semi‐quantitative RT‐PCR was used to quantify CYLD mRNA expression in zebrafish embryos at various developmental stages. We also performed whole‐mount in situ hybridization to further assess the dynamic expression and distribution of CYLD in the entire zebrafish embryos at different stages. In addition, we deleted CYLD in zebrafish with TALENs to investigate its potential impact on embryonic development. Results The expression of CYLD mRNA varied during early embryonic development. The CYLD mRNA localized to the brain and notochord of developing zebrafish embryos. Homozygous deletion of CYLD resulted in embryonic death before 8 h post‐fertilization. Conclusions CYLD appears to play an important role in central nervous system development in zebrafish. Although severe embryonic death restricted analysis of homozygous mutants, further research into the role of CYLD in central nervous system development is warranted.
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Affiliation(s)
- Te Li
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Yiyan Wang
- Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Peking University Genome Editing Research Center, College of Life Sciences, Peking University, Beijing, China
| | - Dengwen Li
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Jun Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.,Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Bo Zhang
- Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Peking University Genome Editing Research Center, College of Life Sciences, Peking University, Beijing, China
| | - Xianfei He
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
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21
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Gupta A, Behl T, Aleya L, Rahman MH, Yadav HN, Pal G, Kaur I, Arora S. Role of UPP pathway in amelioration of diabetes-associated complications. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:19601-19614. [PMID: 33660172 DOI: 10.1007/s11356-021-12781-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 01/29/2021] [Indexed: 06/12/2023]
Abstract
Type 2 diabetes (T2D) is one of the most widely spread metabolic disorder also called as "life style" disease. Due to the alarming number of patients, there is great need to therapies targeting functions which can help in maintaining the homeostasis of glucose levels and improving insulin sensitivity. Detailed analysis was done through various research and review papers which was searched using MEDLINE, BIOSIS, and EMBASE using various keywords. This search retrieved the most appropriate content on these molecules targeting UPP pathway. From this extensive review involving UPP pathway, it was concluded that the role of ubiquitin's is not only limited to neurodegenerative disorders but also plays a critical role in progression of diabetes including obesity, insulin resistance, and various neurogenerative disorders but it also targets proteasomal degradation including mediation of cellular signaling pathways. Thus, drugs targeting UPP not only may show effect against diabetes but also are therapeutically beneficial in the treatment of diabetes-associated complications which may be obtained. Thus, based on the available information and data on UPP functions, it can be concluded that regulation of UPP pathway via downstream regulators mainly E1, E2, and E3 may bring promising results. Drugs targeting these transcriptional factors may emerge as a novel therapy in the treatment of diabetes and diabetes-associated complications.
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Affiliation(s)
- Amit Gupta
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France
| | - Md Habibur Rahman
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Seoul, South Korea
- Department of Pharmacy, Southeast University, Banani, Dhaka, 1213, Bangladesh
| | | | - Giridhari Pal
- Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sandeep Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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22
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Kaushal K, Ramakrishna S. Deubiquitinating Enzyme-Mediated Signaling Networks in Cancer Stem Cells. Cancers (Basel) 2020; 12:E3253. [PMID: 33158118 PMCID: PMC7694198 DOI: 10.3390/cancers12113253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs) have both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Thus, CSCs are considered to be promising therapeutic targets for cancer therapy. The function of CSCs can be regulated by ubiquitination and deubiquitination of proteins related to the specific stemness of the cells executing various stem cell fate choices. To regulate the balance between ubiquitination and deubiquitination processes, the disassembly of ubiquitin chains from specific substrates by deubiquitinating enzymes (DUBs) is crucial. Several key developmental and signaling pathways have been shown to play essential roles in this regulation. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of CSCs. These signaling pathways have been experimentally shown to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. In this review, we focus on the DUBs involved in CSCs signaling pathways, which are vital in regulating their stem-cell fate determination.
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Affiliation(s)
- Kamini Kaushal
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea;
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea;
- College of Medicine, Hanyang University, Seoul 04763, Korea
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23
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Sun T, Liu Z, Yang Q. The role of ubiquitination and deubiquitination in cancer metabolism. Mol Cancer 2020; 19:146. [PMID: 33004065 PMCID: PMC7529510 DOI: 10.1186/s12943-020-01262-x] [Citation(s) in RCA: 270] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.
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Affiliation(s)
- Tianshui Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Zhuonan Liu
- Department of Urology, First Hospital of China Medical University, Shenyang, China
| | - Qing Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China.
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24
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The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGF Signaling. Cancers (Basel) 2020; 12:cancers12082047. [PMID: 32722292 PMCID: PMC7466024 DOI: 10.3390/cancers12082047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/07/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023] Open
Abstract
Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGF)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGF pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers.
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25
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Umemura S, Zhu J, Chahine JJ, Kallakury B, Chen V, Kim IK, Zhang YW, Goto K, He Y, Giaccone G. Downregulation of CYLD promotes IFN-γ mediated PD-L1 expression in thymic epithelial tumors. Lung Cancer 2020; 147:221-228. [PMID: 32738418 DOI: 10.1016/j.lungcan.2020.07.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/09/2020] [Accepted: 07/16/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Recent genomic studies suggest the biological significance of the cylindromatosis (CYLD) gene in thymic epithelial tumors (TETs). CYLD is a crucial regulator of immune response, and we previously reported that CYLD mutation is associated with high PD-L1 expression in thymic carcinoma. Therefore, we wanted to explore the role and mechanism of CYLD in regulating PD-L1 expression in TETs. MATERIALS AND METHODS The role of CYLD in PD-L1 expression was assessed by knockdown of CYLD in TET cells upon stimulation with interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α) or polyinosinic-polycytidylic acid (poly I:C). The molecular mechanism was investigated through analysis of downstream molecules in the STAT1/IRF1 pathway. Moreover, the clinical correlation between low CYLD and high PD-L1 expression, and the clinical impact of CYLD expression were evaluated in tissue microarrays of 105 TET cases. RESULTS CYLD knockdown significantly enhanced the expression of PD-L1 in presence of IFN-γ stimulation in most TET cell lines. However, this phenomenon was not observed in presence of TNF-α stimulation. CYLD knockdown upregulated IFN-γ mediated activation of the STAT1/IRF1 axis, which in turn induced PD-L1 expression. Interestingly, we found a significant association between low CYLD expression and ≥ 50 % PD-L1 expression (p = 0.001). In addition, the average proportion of tumor cells exhibiting PD-L1 staining was significantly higher in the low CYLD expression group (24.7 %) than in the high CYLD expression group (5.2 %) (p = 0.005). There was no correlation between CYLD expression and the frequency of pre-existing paraneoplastic auto-immune diseases. In advanced stages (III/IV), the low CYLD expressing group had numerically worse survival than the high CYLD group (log-rank p = 0.089). CONCLUSIONS Our findings provide insight into the mechanism of regulation of PD-L1 expression by CYLD in TET cells. Tumors with low CYLD expression could be potential targets for PD-1/PD-L1 inhibitors.
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Affiliation(s)
- Shigeki Umemura
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Jianquan Zhu
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA; Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Lung Cancer Center, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Joeffrey J Chahine
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Bhaskar Kallakury
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Vincent Chen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - In-Kyu Kim
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Yu-Wen Zhang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA; Department of Cell Biology, University of Virginia, VA, USA
| | - Koichi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Yongfeng He
- Meyer Cancer Center, Weill Cornel Medicine, NY, USA
| | - Giuseppe Giaccone
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA; Meyer Cancer Center, Weill Cornel Medicine, NY, USA.
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26
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Deng M, Dai W, Yu VZ, Tao L, Lung ML. Cylindromatosis Lysine 63 Deubiquitinase (CYLD) Regulates NF-kB Signaling Pathway and Modulates Fibroblast and Endothelial Cells Recruitment in Nasopharyngeal Carcinoma. Cancers (Basel) 2020; 12:cancers12071924. [PMID: 32708712 PMCID: PMC7409113 DOI: 10.3390/cancers12071924] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/20/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the nasopharynx. Cylindromatosis lysine 63 deubiquitinase (CYLD), a NF-kB inhibitor, was reported as one of the top mutated candidate genes in NPC. NF-kB is an inducible transcription factor, contributing to cancer via regulating inflammation, angiogenesis, cell proliferation, and metastasis. In this study, the impact of CYLD on regulating the NF-kB signaling pathway and its contribution to NPC development was studied using in vitro and in vivo functional assays, together with single cell RNA sequencing to understand the NPC tumor microenvironment. CYLD was downregulated in NPC clinical specimens and multiple cell lines. Functional assays revealed CYLD inhibits NPC cell proliferation and migration in vitro and suppresses NPC tumorigenicity and metastasis in vivo by negatively regulating the NF-kB signaling pathway. Additionally, CYLD was able to inhibit fibroblast and endothelial stromal cell infiltration into the NPC tumor microenvironment. These findings suggest that CYLD inhibits NPC development and provides strong evidence supporting a role for CYLD inhibiting fibroblast and endothelial stromal cell infiltration into NPC via suppressing the NF-kB pathway.
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27
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Li T, Zou C. The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome. Int J Mol Sci 2020; 21:E4842. [PMID: 32650621 PMCID: PMC7402294 DOI: 10.3390/ijms21144842] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/02/2020] [Accepted: 07/05/2020] [Indexed: 12/11/2022] Open
Abstract
Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30-40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.
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Affiliation(s)
| | - Chunbin Zou
- Division of Pulmonary, Allergy, Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA;
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28
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CYLD exaggerates pressure overload-induced cardiomyopathy via suppressing autolysosome efflux in cardiomyocytes. J Mol Cell Cardiol 2020; 145:59-73. [PMID: 32553594 DOI: 10.1016/j.yjmcc.2020.06.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/20/2020] [Accepted: 06/07/2020] [Indexed: 02/06/2023]
Abstract
Deubiquitinating enzymes (DUBs) appear to be a new class of regulators of cardiac homeostasis and disease. However, DUB-mediated signaling in the heart is not well understood. Herein we report a novel mechanism by which cylindromatosis (CYLD), a DUB mediates cardiac pathological remodeling and dysfunction. Cardiomyocyte-restricted (CR) overexpression of CYLD (CR-CYLD) did not cause gross health issues and hardly affected cardiac function up to age of one year in both female and male mice at physiological conditions. However, CR-CYLD overexpression exacerbated pressure overload (PO)-induced cardiac dysfunction associated with suppressed cardiac hypertrophy and increased myocardial apoptosis in mice independent of the gender. At the molecular level, CR-CYLD overexpression enhanced PO-induced increases in poly-ubiquitinated proteins marked by lysine (K)48-linked ubiquitin chains and autophagic vacuoles containing undegraded contents while suppressing autophagic flux. Augmentation of cardiac autophagy via CR-ATG7 overexpression protected against PO-induced cardiac pathological remodeling and dysfunction in both female and male mice. Intriguingly, CR-CYLD overexpression switched the CR-ATG7 overexpression-dependent cardiac protection into myocardial damage and dysfunction associated with increased accumulation of autophagic vacuoles containing undegraded contents in the heart. Genetic manipulation of Cyld in combination with pharmacological modulation of autophagic functional status revealed that CYLD suppressed autolysosomal degradation and promoted cell death in cardiomyocytes. In addition, Cyld gene gain- and/or loss-of-function approaches in vitro and in vivo demonstrated that CYLD mediated cardiomyocyte death associated with impaired reactivation of mechanistic target of rapamycin complex 1 (mTORC1) and upregulated Ras genes from rat brain 7 (Rab7), two key components for autolysosomal degradation. These results demonstrate that CYLD serves as a novel mediator of cardiac pathological remodeling and dysfunction by suppressing autolysosome efflux in cardiomyocytes. Mechanistically, it is most likely that CYLD suppresses autolysosome efflux via impairing mTORC1 reactivation and interrupting Rab7 release from autolysosomes in cardiomyocytes.
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Zou X, Tan Q, Goh BH, Lee LH, Tan KL, Ser HL. ‘Sweeter’ than its name: anti-inflammatory activities of Stevia rebaudiana. ALL LIFE 2020. [DOI: 10.1080/26895293.2020.1771434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Xiaomin Zou
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, 510006 Guangzhou, People’s Republic of China
| | - QiWen Tan
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, 510006 Guangzhou, People’s Republic of China
| | - Bey-Hing Goh
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
- Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Learn-Han Lee
- Institute of Pharmaceutical Science, University of Veterinary and Animal Science, Lahore, Pakistan
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor Darul Ehsan, Malaysia
| | - Kai-Leng Tan
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, 510006 Guangzhou, People’s Republic of China
| | - Hooi-Leng Ser
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, 510006 Guangzhou, People’s Republic of China
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor Darul Ehsan, Malaysia
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Jang JH, Lee HM, Kim H, Cho JH. Molecular cloning and functional analysis of deubiquitinase CYLD in rainbow trout, Oncorhynchus mykiss. FISH & SHELLFISH IMMUNOLOGY 2020; 101:135-142. [PMID: 32224281 DOI: 10.1016/j.fsi.2020.03.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/18/2020] [Accepted: 03/25/2020] [Indexed: 06/10/2023]
Abstract
Deubiquitinase cylindromatosis (CYLD) inhibits MAPK and NF-κB activation pathways by deubiquitinating upstream regulatory factors. Although CYLD has been identified and actively studied in mammals, nothing is known about its putative function in fish. In this study, we identified the gene encoding CYLD (OmCYLD) from rainbow trout, Oncorhynchus mykiss, and examined its role during pathogenic infections. The deduced amino acid sequence of OmCYLD contains conserved CAP-Gly and USP domains. In RTH-149 cells, the expression of OmCYLD was increased by stimulation with Edwardsiella tarda and Streptococcus iniae. Gain-of-function and loss-of-function experiments showed that OmCYLD down-regulates the activation of MAPK and NF-κB and the expression of pro-inflammatory cytokines in E. tarda-stimulated RTH-149 cells. These findings suggest that OmCYLD might function like those of mammals to negatively regulate bacteria-triggered signaling pathway in fish.
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Affiliation(s)
- Ju Hye Jang
- Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, South Korea
| | - Hyang Mi Lee
- Division of Applied Life Science, Gyeongsang National University, Jinju, 52828, South Korea
| | - Hyun Kim
- Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, South Korea
| | - Ju Hyun Cho
- Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, South Korea; Division of Applied Life Science, Gyeongsang National University, Jinju, 52828, South Korea; Division of Life Science, Gyeongsang National University, Jinju, 52828, South Korea.
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Qiu C, Liu K, Zhang S, Gao S, Chen W, Li D, Huang Y. Bisdemethoxycurcumin Inhibits Hepatocellular Carcinoma Proliferation Through Akt Inactivation via CYLD-Mediated Deubiquitination. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:993-1001. [PMID: 32184568 PMCID: PMC7062405 DOI: 10.2147/dddt.s231814] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 02/20/2020] [Indexed: 12/24/2022]
Abstract
Background Bisdemethoxycurcumin (BDMC), a stable bioactive ingredient in curcuminoids, is associated with various antitumor functions, such as proliferation inhibition, metastasis suppression and apoptosis induction, in many cancer types. However, the mechanism of BDMC in hepatocellular carcinoma (HCC) remains unclear. Methods We assessed the toxicity and the inhibitory effect of BDMC in the HepG2 cell line by using CCK-8 and colony formation assays. The regulatory effects of BDMC on Akt and MAPK signaling were investigated by Western blotting and immunoprecipitation. Results We found that the half-maximum inhibitory concentration (IC50) of BDMC after 48 hrs of treatment was 59.13 μM, and BDMC inhibited proliferation in a time- and dose-dependent manner in HepG2 cells. The inhibitory effect was caused by the inactivation of Akt signaling, but not Erk, Jnk or p38 signaling. In addition, the inactivation of Akt signaling was attributed to the inhibition of ubiquitination mediated by K63-Ub but not K48-Ub. Furthermore, we found that BDMC upregulated the expression of CYLD, leading to Akt deubiquitination and inactivation. Conclusion BDMC inhibited HCC cell proliferation, and that this effect was induced by Akt inactivation via CYLD-mediated deubiquitination.
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Affiliation(s)
- Chengjiang Qiu
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Kairui Liu
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Sheng Zhang
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Simin Gao
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People's Republic of China
| | - Weirun Chen
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Dateng Li
- Department of Statistical Science, Southern Methodist University, Dallas, TX 75275, USA
| | - Youxing Huang
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
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Deng L, Meng T, Chen L, Wei W, Wang P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther 2020; 5:11. [PMID: 32296023 PMCID: PMC7048745 DOI: 10.1038/s41392-020-0107-0] [Citation(s) in RCA: 451] [Impact Index Per Article: 90.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/12/2019] [Accepted: 12/17/2019] [Indexed: 02/08/2023] Open
Abstract
Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.
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Affiliation(s)
- Lu Deng
- College of Animal Science and Technology, Northwest A&F University, Yangling Shaanxi, 712100, China.
| | - Tong Meng
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, 389 Xincun Road, Shanghai, China
| | - Lei Chen
- Division of Laboratory Safety and Services, Northwest A&F University, Yangling Shaanxi, 712100, China
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Ping Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, 200092, China.
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Nguyen J, Massoumi R, Alliston T. CYLD, a mechanosensitive deubiquitinase, regulates TGFβ signaling in load-induced bone formation. Bone 2020; 131:115148. [PMID: 31715338 PMCID: PMC7032548 DOI: 10.1016/j.bone.2019.115148] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022]
Abstract
Many signaling pathways involved in bone homeostasis also participate in the anabolic response of bone to mechanical loading. For example, TGFβ signaling coordinates the maintenance of bone mass and bone quality through its effects on osteoblasts, osteoclasts, and osteocytes. TGFβ signaling is also essential for the mechanosensitive formation of new bone. However, the mechanosensitive mechanisms controlling TGFβ signaling in osteocytes remain to be determined, particularly those that integrate TGFβ signaling with other early responses to mechanical stimulation. Here, we used an in vivo mouse hindlimb loading model to identify mechanosensitive molecules in the TGFβ pathway, and MLO-Y4 cells to evaluate their interactions with the prostaglandin E2 (PGE2) pathway, which is well-known for its rapid response to mechanical stimulation and its role in bone anabolism. Although mRNA levels for several TGFβ ligands, receptors, and effectors were unchanged, the level of phosphorylated Smad2/3 (pSmad2/3) was reduced in tibial bone as early as 3 h after early mechanical stimulation. We found that PGE2 and its receptor, EP2, repress pSmad2/3 levels and transactivation of Serpine1 in osteocytes. PGE2 and EP2 control the level of pSmad2/3 through a proteasome-dependent mechanism that relies on the deubiquitinase CYLD. CYLD protein levels were also reduced in the tibiae within 3 h of mechanical loading. Using CYLD-deficient mice, we found that CYLD is required for the rapid load-mediated repression of pSmad2/3 and for load-induced bone formation. These data introduce CYLD as a mechanosensitive deubiquitinase that participates in the prostaglandin-dependent repression of TGFβ signaling in osteocytes.
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Affiliation(s)
- Jacqueline Nguyen
- Department of Orthopaedic Surgery, University of California San Francisco, 94143, USA; Graduate Program in Oral and Craniofacial Sciences, University of California San Francisco, 94143, USA
| | - Ramin Massoumi
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Medicon Village, 22381, Sweden
| | - Tamara Alliston
- Department of Orthopaedic Surgery, University of California San Francisco, 94143, USA; Graduate Program in Oral and Craniofacial Sciences, University of California San Francisco, 94143, USA.
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Komatsu K, Nam DH, Lee JY, Yoneda G, Yan C, Li JD. Vinpocetine Suppresses Streptococcus pneumoniae-Induced Inflammation via Inhibition of ERK1 by CYLD. THE JOURNAL OF IMMUNOLOGY 2020; 204:933-942. [PMID: 31900337 DOI: 10.4049/jimmunol.1901299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/05/2019] [Indexed: 12/21/2022]
Abstract
Otitis media (OM) is the most common bacterial infection in children. It remains a major health problem and a substantial socioeconomic burden. Streptococcus pneumoniae (S. pneumoniae) is one of the most common bacterial pathogens causing OM. Innate inflammatory response plays a critical role in host defense against bacterial pathogens. However, if excessive, it has a detrimental impact on the middle ear, leading to middle ear inflammation, a hallmark of OM. Currently, there has been limited success in developing effective therapeutic agents to suppress inflammation without serious side effects. In this study, we show that vinpocetine, an antistroke drug, suppressed S. pneumoniae-induced inflammatory response in cultured middle ear epithelial cells as well as in the middle ear of mice. Interestingly, vinpocetine inhibited S. pneumoniae-induced inflammation via upregulating a key negative regulator cylindromatosis (CYLD). Moreover, CYLD suppressed S. pneumoniae-induced inflammation via inhibiting the activation of ERK. Importantly, the postinfection administration of vinpocetine markedly inhibited middle ear inflammation induced by S. pneumoniae in a well-established mouse OM model. These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression.
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Affiliation(s)
- Kensei Komatsu
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303
| | - Dae-Hwan Nam
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303
| | - Ji-Yun Lee
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.,College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul 06974, South Korea; and
| | - Go Yoneda
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303
| | - Chen Yan
- Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642
| | - Jian-Dong Li
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303;
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Functional analysis of deubiquitylating enzymes in tumorigenesis and development. Biochim Biophys Acta Rev Cancer 2019; 1872:188312. [DOI: 10.1016/j.bbcan.2019.188312] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/16/2019] [Accepted: 08/16/2019] [Indexed: 02/06/2023]
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Deubiquitinating Enzymes: A Critical Regulator of Mitosis. Int J Mol Sci 2019; 20:ijms20235997. [PMID: 31795161 PMCID: PMC6929034 DOI: 10.3390/ijms20235997] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 12/20/2022] Open
Abstract
Mitosis is a complex and dynamic process that is tightly regulated by a large number of mitotic proteins. Dysregulation of these proteins can generate daughter cells that exhibit genomic instability and aneuploidy, and such cells can transform into tumorigenic cells. Thus, it is important for faithful mitotic progression to regulate mitotic proteins at specific locations in the cells at a given time in each phase of mitosis. Ubiquitin-dependent modifications play critical roles in this process by regulating the degradation, translocation, or signal transduction of mitotic proteins. Here, we review how ubiquitination and deubiquitination regulate the progression of mitosis. In addition, we summarize the substrates and roles of some deubiquitinating enzymes (DUBs) crucial for mitosis and describe how they contribute error correction during mitosis and control the transition between the mitotic phases.
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de Jel MM, Schott M, Lamm S, Neuhuber W, Kuphal S, Bosserhoff AK. Loss of CYLD accelerates melanoma development and progression in the Tg(Grm1) melanoma mouse model. Oncogenesis 2019; 8:56. [PMID: 31591386 PMCID: PMC6779913 DOI: 10.1038/s41389-019-0169-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/24/2019] [Accepted: 09/24/2019] [Indexed: 01/17/2023] Open
Abstract
The deubiquitinase cylindromatosis (CYLD) is a well-known tumor suppressor, found to be down regulated in many cancer types including breast cancer, colon carcinoma and malignant melanoma. CYLD is suppressed in human melanoma cells by the transcriptional repressor SNAIL1 leading to an increase of their proliferative, invasive and migratory potential. To gain additional insights into the distinct function of this tumor suppressor gene a new mouse model Tg(Grm1)Cyld-/- was generated. Herewith, we demonstrate that Cyld-deficiency leads to earlier melanoma onset and accelerated tumor growth and metastasis in the GRM1 melanoma mouse model. First, RNA sequencing data revealed a potential role of CYLD in the regulation of genes involved in proliferation, migration and angiogenesis. Experiments using cell lines generated from both primary and metastatic melanoma tissue of Tg(Grm1) Cyld-/- and Tg(Grm1) Cyld+/+ mice confirmed that loss of CYLD enhances the proliferative and migratory potential, as well as the clonogenicity in vitro. Moreover, we could show that Cyld-knockout leads to increased vasculogenic mimicry and enhanced (lymph-) angiogenesis shown by tube formation assays, immunohistochemistry and mRNA expression analyses. In summary, our findings reveal new functional aspects of CYLD in the process of (lymph-) angiogenesis and demonstrate its importance in the early process of melanoma progression.
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Affiliation(s)
- Miriam Martha de Jel
- Institute for Biochemistry, University of Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Mandy Schott
- Institute for Biochemistry, University of Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Susanne Lamm
- Institute for Biochemistry, University of Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Winfried Neuhuber
- Institute for Anatomy, University of Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Silke Kuphal
- Institute for Biochemistry, University of Erlangen-Nürnberg (FAU), Erlangen, Germany
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Zhang J, Zhou Q, Wang H, Huang M, Shi J, Han F, Cai W, Li Y, He T, Hu D. MicroRNA-130a has pro-fibroproliferative potential in hypertrophic scar by targeting CYLD. Arch Biochem Biophys 2019; 671:152-161. [PMID: 31283910 DOI: 10.1016/j.abb.2019.07.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 06/26/2019] [Accepted: 07/04/2019] [Indexed: 02/08/2023]
Abstract
Hypertrophic scars are dermal fibrosis diseases that protrude from the surface of the skin and irregularly extend to the periphery, seriously affecting the appearance and limb function of the patient. In this study, we found that microRNA-130a (miR-130a) was increased in hypertrophic scar tissues and derived primary fibroblasts, accompanied by up-regulation of collagen1/3 and α-SMA. Inhibition of miR-130a in hypertrophic scars fibroblasts suppressed the expression of collagen1/3 and α-SMA as well as the cell proliferation. Bioinformatics analysis combined with luciferase reporter gene assay results indicated that CYLD was a target gene of miR-130a, and the miR-130a mimic could reduce the level of CYLD. In contrast to miR-130a, the expression of CYLD was downregulated in hypertrophic scars and their derived fibroblasts. Overexpressing CYLD inhibited the expression of collagen 1/3 and α-SMA, slowed cell proliferation, and inhibited Akt activity. As expected, further study showed that the overexpression of CYLD could prevent the pro-fibroproliferative effects of miR-130a. Consistent with the in vitro results, the inhibitor of miR-130a effectively ameliorated excessive collagen deposition in bleomycin-induced skin fibrosis mouse model. Taken together, our results indicate that miR-130a promotes collagen secretion, myofibroblast transformation and cell proliferation by targeting CYLD and enhancing Akt activity. Therefore, the miR-130a/CYLD/Akt pathway may serve as a novel entry point for future skin fibrosis research.
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Affiliation(s)
- Jian Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Qin Zhou
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Hongtao Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Meiling Huang
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Jihong Shi
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Fu Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Weixia Cai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Yan Li
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Ting He
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China.
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Yin F, He H, Zhang B, Zheng J, Wang M, Zhang M, Cui H. Effect of Deubiquitinase Ovarian Tumor Domain-Containing Protein 5 (OTUD5) on Radiosensitivity of Cervical Cancer by Regulating the Ubiquitination of Akt and its Mechanism. Med Sci Monit 2019; 25:3469-3475. [PMID: 31075090 PMCID: PMC6525574 DOI: 10.12659/msm.912904] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the role of deubiquitinase [ovarian tumor domain-containing protein 5 (OTUD5)] in regulating Akt ubiquitination and its effect on the radiosensitivity of cervical cancer. MATERIAL AND METHODS Cervical cancer C33A cells were cultured, and then 2 groups of cells (overexpressed cells and silenced cells) were established by overexpressing and silencing OTUD5 gene. Next, quantitative polymerase chain reaction (qPCR) was employed to detect the expression level of OTUD5 in cells in each group. Co-immunoprecipitation and Western blot (WB) analysis were applied to measure the expression level of phosphorylated protein kinase B (Akt) and the level of ubiquitination. The sensitivity of cells to radiotherapy in each group was detected via clone-forming efficiency assay. After that, Statistical Product and Service Solutions (SPSS) 17.0 software was employed for analyses. The t test, one-way analysis of variance (ANOVA), and p test were used. P<0.05 suggested that a difference was statistically significant. RESULTS The levels of phosphorylated Akt and ubiquitination in OTUD5-overexpressed C33A cells were lower than those in the OTUD5-silenced group and control group. The sensitivity of OTUD5-overexpressed C33A cells to radiotherapy was higher than that of the OTUD5-silenced group and control group. CONCLUSIONS OTUD5 affects the radiosensitivity of cervical cancer through the regulation of Akt deubiquitination.
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Affiliation(s)
- Fengling Yin
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China (mainland)
| | - Houguang He
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China (mainland)
| | - Bei Zhang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China (mainland)
| | - Jianhua Zheng
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China (mainland)
| | - Meng Wang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China (mainland)
| | - Meng Zhang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China (mainland)
| | - Hongxia Cui
- Department of Oncology, Jining First People's Hospital, Jining, Shandong, China (mainland)
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Wang A, Zhu F, Liang R, Li D, Li B. Regulation of T cell differentiation and function by ubiquitin-specific proteases. Cell Immunol 2019; 340:103922. [PMID: 31078284 DOI: 10.1016/j.cellimm.2019.103922] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 05/02/2019] [Indexed: 12/13/2022]
Abstract
T cells play critical roles in immune responses to pathogens, autoimmunity, and antitumor immunity. During the past few decades, increasing numbers of studies have demonstrated the significance of protein ubiquitination in T cell-mediated immunity. Several E3 ubiquitin ligases and deubiquitinases (DUBs) have been identified as either positive or negative regulators of T cell development and function. In this review, we mainly focus on the roles of DUBs (especially ubiquitin-specific proteases (USPs)) in modulating T cell differentiation and function, as well as the molecular mechanisms. Understanding how T cell development and function is regulated by ubiquitination and deubiquitination will provide novel strategies for treating infection, autoimmune diseases, and cancer.
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Affiliation(s)
- Aiting Wang
- Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China
| | - Fangming Zhu
- Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Bio-energy Crops, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Rui Liang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China
| | - Dan Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China
| | - Bin Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
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Abstract
In addition to the pivotal roles for histone methylation in the transcriptional regulation, emerging evidence suggests important roles for methylation of non-histone proteins in response to extra-cellular stimulatory events, with implications in governing tumorigenesis. Among the increasing list of non-histone proteins targeted for methylation, the tri-lysine-methylation modification of AKT has been recently identified to fine-tune its kinase activity and oncogenic functions. Moreover, our results implicate the histone methyltransferase SETDB1 as the methyltransferase modifying and activating AKT in a PI3K dependent manner. As such, the oncogenic function of SETDB1 in various cancers may be attributed to tumorigenesis, at least in part, through activating AKT. Therefore, targeting SETDB1, which modulates both epigenetic marks and AKT kinase activity simultaneously, is a potential strategy for novel cancer therapeutics.
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Affiliation(s)
- Jianping Guo
- a Precision Medicine Institute, The First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong , China.,b Department of Pathology, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
| | - Wenyi Wei
- b Department of Pathology, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
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Jiang Y, Su S, Zhang Y, Qian J, Liu P. Control of mTOR signaling by ubiquitin. Oncogene 2019; 38:3989-4001. [PMID: 30705402 PMCID: PMC6621562 DOI: 10.1038/s41388-019-0713-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 12/21/2022]
Abstract
The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation of the mTOR signaling is observed in virtually all solid tumors and has been an attractive drug target. In addition to changes at genetic levels, aberrant activation of the mTOR signaling is also a result from dysregulated posttranslational modifications on key pathway members, such as phosphorylation that has been extensively studied. Emerging evidence also supports a critical role for ubiquitin-mediated modifications in dynamically regulating the mTOR signaling pathway, while a comprehensive review for relevant studies is missing. In this review, we will summarize characterized ubiquitination events on major mTOR signaling components, their modifying E3 ubiquitin ligases, deubiquitinases and corresponding pathophysiological functions. We will also reveal methodologies that have been used to identify E3 ligases or DUBs to facilitate the search for yet-to-be discovered ubiquitin-mediated regulatory mechanisms in mTOR signaling. We hope that our review and perspectives provide rationales and strategies to target ubiquitination for inhibiting mTOR signaling to treat human diseases.
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Affiliation(s)
- Yao Jiang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Siyuan Su
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yanqiong Zhang
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Jiayi Qian
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Pengda Liu
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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Shukla SK, Rafiq K. Proteasome biology and therapeutics in cardiac diseases. Transl Res 2019; 205:64-76. [PMID: 30342797 PMCID: PMC6372329 DOI: 10.1016/j.trsl.2018.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 08/30/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023]
Abstract
The ubiquitin proteasome system (UPS) is the major pathway for intracellular protein degradation in most organs, including the heart. UPS controls many fundamental biological processes such as cell cycle, cell division, immune responses, antigen presentation, apoptosis, and cell signaling. The UPS not only degrades substrates but also regulates activity of gene transcription at the post-transcription level. Emerging evidence suggests that impairment of UPS function is sufficient to cause a number of cardiac diseases, including heart failure, cardiomyopathies, hypertrophy, atrophy, ischemia-reperfusion, and atherosclerosis. Alterations in the expression of UPS components, changes in proteasomal peptidase activities and increased ubiquitinated and oxidized proteins have also been detected in diabetic cardiomyopathy (DCM). However, the pathophysiological role of the UPS in DCM has not been examined. Recently, in vitro and in vivo studies have proven highly valuable in assessing effects of various stressors on the UPS and, in some cases, suggesting a causal link between defective protein clearance and disease phenotypes in different cardiac diseases, including DCM. Translation of these findings to human disease can be greatly strengthened by corroboration of discoveries from experimental model systems using human heart tissue from well-defined patient populations. This review will summarize the general role of the UPS in different cardiac diseases, with major focus on DCM, and on recent advances in therapeutic development.
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Affiliation(s)
- Sanket Kumar Shukla
- Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Khadija Rafiq
- Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Tang Y, Reissig S, Glasmacher E, Regen T, Wanke F, Nikolaev A, Gerlach K, Popp V, Karram K, Fantini MC, Schattenberg JM, Galle PR, Neurath MF, Weigmann B, Kurschus FC, Hövelmeyer N, Waisman A. Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis. Gastroenterology 2019; 156:692-707.e7. [PMID: 30315770 DOI: 10.1053/j.gastro.2018.10.023] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS The CYLD lysine 63 deubiquitinase gene (CYLD) encodes tumor suppressor protein that is mutated in familial cylindromatosus, and variants have been associated with Crohn disease (CD). Splice forms of CYLD that lack exons 7 and 8 regulate transcription factors and functions of immune cells. We examined the expression of splice forms of CYLD in colon tissues from patients with CD and their effects in mice. METHODS We performed immunohistochemical analyses of colon tissues from patients with untreated CD and patients without inflammatory bowel diseases (controls). We obtained mice that expressed splice forms of CYLD (sCYLD mice) without or with SMAD7 (sCYLD/SMAD7 mice) from transgenes and CYLD-knockout mice (with or without transgenic expression of SMAD7) and performed endoscopic analyses. Colitis was induced in Rag1-/- mice by transfer of CD4+ CD62L+ T cells from C57/Bl6 or transgenic mice. T cells were isolated from mice and analyzed by flow cytometry and quantitative real-time polymerase chain reaction and intestinal tissues were analyzed by histology and immunohistochemistry. CYLD forms were expressed in mouse embryonic fibroblasts, primary T cells, and HEK293T cells, which were analyzed by immunoblot, mobility shift, and immunoprecipitation assays. RESULTS The colonic lamina propria from patients with CD was infiltrated by T cells and had higher levels of sCYLD (but not full-length CYLD) and SMAD7 than tissues from controls. Incubation of mouse embryonic fibroblasts and T cells with transforming growth factor β increased their production of sCYLD and decreased full-length CYLD. Transgenic expression of sCYLD and SMAD7 in T cells prevented the differentiation of regulatory T cells and T-helper type 17 cells and increased the differentiation of T-helper type 1 cells. The same effects were observed in colon tissues from sCYLD/SMAD7 mice but not in those from CYLD-knockout SMAD7 mice. The sCYLD mice had significant increases in the numbers of T-helper type 1 cells and CD44high CD62Llow memory-effector CD4+ T cells in the spleen and mesenteric lymph nodes compared with wild-type mice; sCYLD/SMAD7 mice had even larger increases. The sCYLD/SMAD7 mice spontaneously developed severe colitis, with infiltration of the colon by dendritic cells, neutrophils, macrophages, and CD4+ T cells and increased levels of Ifng, Il6, Il12a, Il23a, and Tnf mRNAs. Co-transfer of regulatory T cells from wild-type, but not from sCYLD/SMAD7, mice prevented the induction of colitis in Rag1-/- mice by CD4+ T cells. We found increased levels of poly-ubiquitinated SMAD7 in sCYLD CD4+ T cells. CYLD formed a nuclear complex with SMAD3, whereas sCYLD recruited SMAD7 to the nucleus, which inhibited the expression of genes regulated by SMAD3 and SMAD4. We found that sCYLD mediated lysine 63-linked ubiquitination of SMAD7. The sCYLD-SMAD7 complex inhibited transforming growth factor β signaling in CD4+ T cells. CONCLUSIONS Levels of the spliced form of CYLD are increased in colon tissues from patients with CD. sCYLD mediates ubiquitination and nuclear translocation of SMAD7 and thereby decreases transforming growth factor β signaling in T cells. This prevents immune regulatory mechanisms and leads to colitis in mice.
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Affiliation(s)
- Yilang Tang
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Sonja Reissig
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Elke Glasmacher
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, Garching, Germany
| | - Tommy Regen
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Florian Wanke
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Alexei Nikolaev
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Katharina Gerlach
- Department of Internal Medicine I, University Hospital Erlangen, University Erlangen-Nürnberg, Erlangen, Germany
| | - Vanessa Popp
- Department of Internal Medicine I, University Hospital Erlangen, University Erlangen-Nürnberg, Erlangen, Germany
| | - Khalad Karram
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Massimo C Fantini
- Department of Systems Medicine, University of Tor Vergata, Rome, Italy
| | - Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Peter R Galle
- Department of Internal Medicine I, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Markus F Neurath
- Department of Internal Medicine I, University Hospital Erlangen, University Erlangen-Nürnberg, Erlangen, Germany
| | - Benno Weigmann
- Department of Internal Medicine I, University Hospital Erlangen, University Erlangen-Nürnberg, Erlangen, Germany
| | - Florian C Kurschus
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Nadine Hövelmeyer
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany.
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45
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Genome-wide association analysis for body weight identifies candidate genes related to development and metabolism in rainbow trout (Oncorhynchus mykiss). Mol Genet Genomics 2019; 294:563-571. [PMID: 30635785 DOI: 10.1007/s00438-018-1518-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 12/03/2018] [Indexed: 01/12/2023]
Abstract
Growth is one of the most important traits from both a physiological and economic perspective in aquaculture species. Thus, identifying the genomic regions and genes underpinning genetic variation for this trait is of particular interest in several fish species, including rainbow trout. In this work, we perform a genome-wide association study (GWAS) to identify the genomic regions associated with body weight at tagging (BWT) and at 18 months (BW18M) using a dense SNP panel (57 k) and 4596 genotyped rainbow trout from 105 full-sib families belonging to a Chilean breeding population. Analysis was performed by means of single-step GBLUP approach. Genetic variance explained by 20 adjacent SNP windows across the whole genome is reported. To further explore candidate genes, we focused on windows that explained the highest proportion of genetic variance in the top 10 chromosomes for each trait. The main window from the top 10 chromosomes was explored by BLAST using the first and last SNP position of each window to determine the target nucleotide sequence. As expected, the percentage of genetic variance explained by windows was relatively low, due to the polygenic nature of body weight. The most important genomic region for BWT and BW18M were located on chromosomes 15 and 24 and they explained 2.14% and 3.02% of the genetic variance for each trait, respectively. Candidate genes including several growth factors, genes involved in development of skeletal muscle and bone tissue and nutrient metabolism were identified within the associated regions for both traits BWT and BW18M. These results indicate that body weight is polygenic in nature in rainbow trout, with the most important loci explaining as much as 3% of the genetic variance for the trait. The genes identified here represent good candidates for further functional validation to uncover biological mechanisms underlying variation for growth in rainbow trout.
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Wang S, Ekoue DN, Raj GV, Kittler R. Targeting the turnover of oncoproteins as a new avenue for therapeutics development in castration-resistant prostate cancer. Cancer Lett 2018; 438:86-96. [PMID: 30217566 PMCID: PMC6186492 DOI: 10.1016/j.canlet.2018.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/23/2018] [Accepted: 09/03/2018] [Indexed: 12/19/2022]
Abstract
The current therapeutic armamentarium for castration-resistant prostate cancer (CRPC) includes second-generation agents such as the Androgen Receptor (AR) inhibitor enzalutamide and the androgen synthesis inhibitor abiraterone acetate, immunotherapies like sipuleucel-T, chemotherapies including docetaxel and cabazitaxel and the radiopharmaceutical radium 223 dichloride. However, relapse of CRPC resistant to these therapeutic modalities occur rapidly. The mechanisms of resistance to these treatments are complex, including specific mutations or alternative splicing of oncogenic proteins. An alternative approach to treating CRPC may be to target the turnover of these molecular drivers of CRPC. In this review, the mechanisms by which protein stability of several oncoproteins such as AR, ERG, GR, CYP17A1 and MYC, will be discussed, as well as how these findings could be translated into novel therapeutic agents.
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Affiliation(s)
- Shan Wang
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Dede N Ekoue
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ganesh V Raj
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ralf Kittler
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Xie S, Wu Y, Hao H, Li J, Guo S, Xie W, Li D, Zhou J, Gao J, Liu M. CYLD deficiency promotes pancreatic cancer development by causing mitotic defects. J Cell Physiol 2018; 234:9723-9732. [PMID: 30362575 DOI: 10.1002/jcp.27658] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/02/2018] [Indexed: 12/22/2022]
Abstract
Successful treatment of pancreatic cancer, which has the highest mortality rate among all types of malignancies, has challenged oncologists for decades, and early detection would undoubtedly increase favorable patient outcomes. The identification of proteins involved in pancreatic cancer progression could lead to biomarkers for early detection of this disease. This study identifies one potential candidate, cylindromatosis (CYLD), a deubiquitinase and microtubule-binding protein that plays a suppressive role in pancreatic cancer development. In pancreatic cancer samples, downregulation of CYLD expression resulted from a loss in the copy number of the CYLD gene; additionally, reduced expression of CYLD negatively correlated with the clinicopathological parameters. Further study demonstrated that CYLD deficiency promoted colony formation in vitro and pancreatic cancer growth in vivo. Mechanistic studies revealed that CYLD is essential for spindle orientation and properly oriented cell division; CYLD deficiency resulted in a substantial increase in chromosome missegregation. Taken together, these data indicate a critical role for CYLD in suppressing pancreatic tumorigenesis, implicating its potential as a biomarker for early detection of pancreatic cancer and a prognostic indicator of patient outcomes.
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Affiliation(s)
- Songbo Xie
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Yuhan Wu
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Huijie Hao
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of the Ministry of Education, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China
| | - Jingrui Li
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Song Guo
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of the Ministry of Education, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China
| | - Wei Xie
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Dengwen Li
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of the Ministry of Education, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China
| | - Jun Zhou
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China.,State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of the Ministry of Education, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China
| | - Jinmin Gao
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Min Liu
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong, China
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Spaan I, Raymakers RA, van de Stolpe A, Peperzak V. Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential. J Hematol Oncol 2018; 11:67. [PMID: 29776381 PMCID: PMC5960217 DOI: 10.1186/s13045-018-0615-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/06/2018] [Indexed: 12/18/2022] Open
Abstract
Multiple myeloma is the second most frequent hematological malignancy in the western world and remains incurable, predominantly due to acquired drug resistance and disease relapse. The highly conserved Wnt signal transduction pathway, which plays a key role in regulating cellular processes of proliferation, differentiation, migration, and stem cell self-renewal, is associated with multiple aspects of disease. Bone homeostasis is severely disturbed by Wnt antagonists that are secreted by the malignant plasma cells in the bone marrow. In the vast majority of patients, this results in osteolytic bone disease, which is associated with bone pain and pathological fractures and was reported to facilitate disease progression. More recently, cumulative evidence also indicates the importance of intrinsic Wnt signaling in the survival of multiple myeloma cells. However, Wnt pathway-activating gene mutations could not be identified. The search for factors or processes responsible for Wnt pathway activation currently focuses on aberrant ligand levels in the bone marrow microenvironment, increased expression of Wnt transcriptional co-factors and associated micro-RNAs, and disturbed epigenetics and post-translational modification processes. Furthermore, Wnt pathway activation is associated with acquired cell adhesion-mediated resistance of multiple myeloma cells to conventional drug therapies, including doxorubicin and lenalidomide. In this review, we present an overview of the relevance of Wnt signaling in multiple myeloma and highlight the Wnt pathway as a potential therapeutic target for this disease.
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Affiliation(s)
- Ingrid Spaan
- Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
| | - Reinier A Raymakers
- Department of Hematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
| | - Anja van de Stolpe
- Molecular Diagnostics, Philips Research, High Tech Campus 11, 5656 AE, Eindhoven, the Netherlands
| | - Victor Peperzak
- Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands.
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49
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Li S, Zhao J, Shang D, Kass DJ, Zhao Y. Ubiquitination and deubiquitination emerge as players in idiopathic pulmonary fibrosis pathogenesis and treatment. JCI Insight 2018; 3:120362. [PMID: 29769446 DOI: 10.1172/jci.insight.120362] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is associated with aberrant activation of TGF-β, myofibroblast differentiation, and abnormal extracellular matrix (ECM) production. Proper regulation of protein stability is important for maintenance of intracellular protein homeostasis and signaling. Ubiquitin E3 ligases mediate protein ubiquitination, and deubiquitinating enzymes (DUBs) reverse the process. The role of ubiquitin E3 ligases and DUBs in the pathogenesis of IPF is relatively unexplored. In this review, we provide an overview of how ubiquitin E3 ligases and DUBs modulate pulmonary fibrosis through regulation of both TGF-β-dependent and -independent pathways. We also summarize currently available small-molecule inhibitors of ubiquitin E3 ligases and DUBs as potential therapeutic strategies for the treatment of IPF.
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Affiliation(s)
- Shuang Li
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jing Zhao
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Dong Shang
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Daniel J Kass
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yutong Zhao
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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50
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Deubiquitinating enzyme USP3 controls CHK1 chromatin association and activation. Proc Natl Acad Sci U S A 2018; 115:5546-5551. [PMID: 29735693 DOI: 10.1073/pnas.1719856115] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Checkpoint kinase 1 (CHK1), a Ser/Thr protein kinase, is modified by the K63-linked ubiquitin chain in response to genotoxic stress, which promotes its nuclear localization, chromatin association, and activation. Interestingly, this bulky modification is linked to a critical residue, K132, at the kinase active site. It is unclear how this modification affects the kinase activity and how it is removed to enable the release of CHK1 from chromatin. Herein, we show that the K63-linked ubiquitin chain at CHK1's K132 residue has an inhibitory effect on the kinase activity. Furthermore, we demonstrate that this modification can be removed by ubiquitin-specific protease 3 (USP3), a deubiquitinating enzyme that targets K63-linked ubiquitin chains. Wild-type USP3, but not the catalytically defective or nuclear localization sequence-deficient mutants, reduced CHK1 K63-linked ubiquitination. Conversely, USP3 knockdown elevated K63-linked ubiquitination of the kinase, leading to prolonged CHK1 chromatin association and phosphorylation. Paradoxically, by removing the bulky ubiquitin chain at the active site, USP3 also increased the accessibility of CHK1 to its substrates. Thus, our findings on the dual roles of USP3 (namely, one to release CHK1 from the chromatin and the other to open up the active site) provide further insights into the regulation of CHK1 following DNA damage.
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