Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China.
Cancer Res. 2020 Jun 1;80(11):2204-2216. doi: 10.1158/0008-5472.CAN-19-2388. Epub 2020 Mar 26.
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 and . 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.
Yes 相关蛋白 (YAP) 和其同源蛋白，PDZ 结合基序的转录共激活因子 (TAZ)，在促进肝细胞癌的进展中起着关键作用。然而，导致 YAP/TAZ 在肝细胞癌中异常激活的调控机制尚不清楚。在这项研究中，我们全面分析了去泛素化酶 (DUB) 对肝细胞癌模型中 YAP/TAZ 的转录活性和蛋白丰度的贡献，并鉴定出泛素特异性肽酶 10 (USP10) 是一种有效的 YAP/TAZ 激活 DUB。从机制上讲，USP10 通过逆转其蛋白水解泛素化作用直接与 YAP/TAZ 相互作用并稳定其蛋白。USP10 的耗竭增强了 YAP/TAZ 的多泛素化，促进了它们的蛋白酶体降解，并最终阻止了肝细胞癌的增殖。和。USP10 的表达水平与肝细胞癌患者样本以及 N-亚硝二乙胺 (DEN) 诱导的肝癌小鼠模型中 YAP/TAZ 的丰度呈正相关。总之，这项研究确立了 USP10 与肝细胞癌细胞中高活性 YAP/TAZ 之间的因果关系，并为针对携带高 YAP/TAZ 水平的肝细胞癌患者的潜在治疗干预提供了依据。意义：这些发现确定了 USP10 是 YAP/TAZ 的 DUB 及其在肝细胞癌进展中的作用，这可能成为肝细胞癌治疗的潜在治疗靶点。
