Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1

The deubiquitinating enzyme USP46 (ubiquitin-specific protease 46) is implicated in various cancers. However, its role and regulatory mechanism in HCC (hepatocellular carcinoma) are still unknown. In this study, we showed that USP46 is downregulated in HCC tissues and that low USP46 levels are associated with poor prognosis in HCC patients. In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo. Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1. Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression. Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression. Finally, we demonstrated that USP46 stabilizes the MST1 protein by directly binding to it and decreasing its ubiquitination. Taken together, our results demonstrated that USP46 may be a novel tumor suppressor in HCC. Moreover, USP46 acts as a deubiquitinating enzyme of MST1 to potentiate MST1 kinase activity to suppress tumor growth and metastasis, indicating that USP46 activation may represent a potential treatment strategy for HCC. Proposed model of USP46-mediated suppression of hepatocellular carcinoma progression by stabilizing MST1. In this study, we demonstrated that USP46 directly interacts with MST1. USP46 inhibits the ubiquitination of MST1 and stabilizes the MST1 protein. USP46-mediated increases in MST1 cause a decrease in YAP1, suppressing proliferation and metastasis of HCC cells. [Display omitted] •Low USP46 level is correlated with poor prognosis in HCC.•USP46 suppresses the proliferation and metastasis of HCC.•USP46 suppress the progression of HCC by inhibiting the expression of YAP1.•MST1 mediates the regulation of USP46 on YAP1.•USP46 stabilized MST1 protein through inhibiting its ubiquitination and degradation.