Huang Lei, Yuan Wenying, Li Xinying, Liu Yixia, Wan Rui, Ma Xiuqing, Liu Tongzheng, Liang Junjie, Zhu Yingjie
College of Pharmacy / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangdong, 510632, China.
Heze Traditional Chinese Medicine Hospital, Shandong, 274000, China.
Cell Death Discov. 2025 Apr 30;11(1):212. doi: 10.1038/s41420-025-02493-x.
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, frequently characterized by high expression and activation of Yes-associated protein 1 (YAP1), a key effector in the Hippo signaling pathway. Despite its crucial role in HCC progression, effective therapies directly targeting YAP1 remain challenging, underscoring the need to explore the regulatory mechanisms underlying its aberrant expression and activation. In this study, we identify cyclin-dependent kinase 4 and 6 (CDK4/6) as uncharacterized regulators of YAP1 in HCC. Genetic ablation or pharmacological inhibition of CDK4/6 significantly destabilizes YAP1 and attenuates its oncogenic functions both in vitro and in vivo. Furthermore, we establish DUB3 as a bona fide deubiquitinase of YAP1. Mechanistically, CDK4/6 directly phosphorylates DUB3, enhancing its deubiquitinase activity towards YAP1, which promotes tumor growth and contributes to chemo-resistance in HCC. Collectively, our findings unveil the previously unrecognized function and significance of the CDK4/6-DUB3 axis in stabilizing YAP1 and provide a rationale for potential therapeutic interventions in the treatment of HCC.
肝细胞癌（HCC）是最致命的恶性肿瘤之一，其特征通常是Yes相关蛋白1（YAP1）高表达和激活，YAP1是Hippo信号通路中的关键效应因子。尽管YAP1在HCC进展中起关键作用，但直接靶向YAP1的有效疗法仍然具有挑战性，这突出了探索其异常表达和激活背后调控机制的必要性。在本研究中，我们确定细胞周期蛋白依赖性激酶4和6（CDK4/6）是HCC中YAP1未被表征的调节因子。CDK4/6的基因敲除或药物抑制显著使YAP1不稳定，并在体外和体内减弱其致癌功能。此外，我们确定DUB3是YAP1真正的去泛素化酶。从机制上讲，CDK4/6直接磷酸化DUB3，增强其对YAP1的去泛素化酶活性，这促进肿瘤生长并导致HCC的化疗耐药性。总体而言，我们的研究结果揭示了CDK4/6-DUB3轴在稳定YAP1方面以前未被认识的功能和意义，并为HCC治疗中的潜在治疗干预提供了理论依据。
