The deubiquitinating enzyme ATXN3 promotes hepatocellular carcinoma progression by stabilizing TAZ.

Abstract

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.