USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ
USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ
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USP10 通过去泛素化和稳定 YAP/TAZ 促进肝细胞癌的增殖
DOI：
10.1158/0008-5472.can-19-2388
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发表时间：
2020-03
期刊：
影响因子：
11.2
通讯作者：
Yang Bo
中科院分区：
文献类型：
--
作者：
Zhu Hong;Yan Fangjie;Yuan Tao;Qian Meijia;Zhou Tianyi;Dai Xiaoyang;Cao Ji;Ying Meidan;Dong Xiaowu;He Qiaojun;Yang Bo
这些发现确定USP 10作为雅普/TAZ的DUB及其在肝细胞癌进展中的作用，其可能作为肝细胞癌治疗的潜在治疗靶点。是细胞相关蛋白（雅普）及其辅因子（TAZ）在肝细胞癌的发生发展中起着重要的作用。然而，肝细胞癌中雅普/TAZ异常激活的调控机制尚不清楚。在这项研究中，我们在肝细胞癌模型中全面分析了去泛素化酶（DUB）对雅普/TAZ转录活性和蛋白丰度的贡献，并鉴定了泛素特异性肽酶10（USP 10）作为一种有效的雅普/TAZ激活DUB。从机制上讲，USP 10通过逆转其蛋白水解泛素化直接与雅普/TAZ相互作用并稳定它们。USP 10的缺失增强了雅普/TAZ的多聚泛素化，促进了它们的蛋白酶体降解，并最终抑制了体外和体内肝细胞癌的增殖。在肝细胞癌患者样品以及N-亚硝基二乙胺（DEN）诱导的肝癌小鼠模型中，USP 10的表达水平与雅普/TAZ的丰度正相关。总的来说，本研究确立了USP 10与肝细胞癌细胞中过度活化的雅普/TAZ之间的因果关系，并为治疗携带高水平雅普/TAZ的肝细胞癌患者的潜在治疗干预提供了理论基础。重要性：这些发现确定USP 10作为雅普/TAZ的DUB及其在肝细胞癌进展中的作用，其可能作为肝细胞癌治疗的潜在治疗靶点。
These findings identify USP10 as a DUB of YAP/TAZ and its role in hepatocellular carcinoma progression, which may serve as a potential therapeutic target for hepatocellular carcinoma treatment. Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma. However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in hepatocellular carcinoma remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in hepatocellular carcinoma models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of hepatocellular carcinoma in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in hepatocellular carcinoma patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in hepatocellular carcinoma cells and provides a rationale for potential therapeutic interventions in the treatment of patients with hepatocellular carcinoma harboring a high level of YAP/TAZ. Significance: These findings identify USP10 as a DUB of YAP/TAZ and its role in hepatocellular carcinoma progression, which may serve as a potential therapeutic target for hepatocellular carcinoma treatment.
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影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
14.8
作者：
Weisberg EL;Schauer NJ;Yang J;Lamberto I;Doherty L;Bhatt S;Nonami A;Meng C;Letai A;Wright R;Tiv H;Gokhale PC;Ritorto MS;De Cesare V;Trost M;Christodoulou A;Christie A;Weinstock DM;Adamia S;Stone R;Chauhan D;Anderson KC;Seo HS;Dhe-Paganon S;Sattler M;Gray NS;Griffin JD;Buhrlage SJ
通讯作者：
Buhrlage SJ
理解Kaplan-Meier曲线的实用指南。
影响因子：
3.4
作者：
Rich, Jason T.;Neely, J. Gail;Paniello, Randal C.;Voelker, Courtney C. J.;Nussenbaum, Brian;Wang, Eric W.
通讯作者：
Wang, Eric W.
DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
5.1
作者：
Marrero, Jorge A;Pelletier, Shawn
通讯作者：
Pelletier, Shawn