Peng Yuanhao, Nie Hui, Kang Kuo, Li Xuanxuan, Tao Yongguang, Zhou Yangying
Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China.
Cancer Gene Ther. 2025 Jan;32(1):136-145. doi: 10.1038/s41417-024-00869-2. Epub 2024 Dec 13.
Hepatocellular carcinoma (HCC) was a primary cause of cancer-related morbidity and mortality in China. ATXN3 was a deubiquitinase (DUB) associated with spinocerebellar ataxia, widely expressed in the cytoplasm and nucleus of cells in the central nervous system and other tissues. The crucial role of the Hippo pathway in tumorigenesis has been established, among which TAZ served as one of the key molecules. However, the mechanisms underlying the deubiquitinase and TAZ in HCC remained largely unknown. In the present study, we explored that ATXN3 was overexpressed in HCC. ATXN3 promoted the proliferation, migration, invasion, and tumorigenic ability of HCC in vitro and in vivo. Besides, we explored that ATXN3 was positively associated with TAZ in HCC. ATXN3 could interact with, stabilize, and deubiquitylate TAZ in a deubiquitylase-dependent manner. Specifically, this interaction was primarily mediated by the C-terminal domain of TAZ and Josephin domain of ATXN3, thereby inhibiting the K48-linked ubiquitin chain on TAZ. Furthermore, we demonstrated that ATXN3 promoted the occurrence and development of HCC by regulating TAZ. Therefore, our study revealed the oncogenic function of ATXN3 and an interesting deubiquitination mechanism of ATXN3 and TAZ in HCC, providing new insights into the diagnosis and treatment of HCC.
肝细胞癌（HCC）是中国癌症相关发病和死亡的主要原因。ATXN3是一种与脊髓小脑共济失调相关的去泛素化酶（DUB），在中枢神经系统和其他组织的细胞胞质和细胞核中广泛表达。Hippo信号通路在肿瘤发生中的关键作用已得到证实，其中TAZ是关键分子之一。然而，去泛素化酶和TAZ在HCC中的潜在机制仍 largely未知。在本研究中，我们发现ATXN3在HCC中过表达。ATXN3在体外和体内均促进HCC的增殖、迁移、侵袭和致瘤能力。此外，我们发现ATXN3在HCC中与TAZ呈正相关。ATXN3可以以去泛素化酶依赖的方式与TAZ相互作用、使其稳定并去泛素化。具体而言，这种相互作用主要由TAZ的C末端结构域和ATXN3的Josephin结构域介导，从而抑制TAZ上K48连接的泛素链。此外，我们证明ATXN3通过调节TAZ促进HCC的发生和发展。因此，我们的研究揭示了ATXN3的致癌功能以及ATXN3和TAZ在HCC中有趣的去泛素化机制，为HCC的诊断和治疗提供了新的见解。
