USP39 stabilizes β-catenin by deubiquitination and suppressing E3 ligase TRIM26 pre-mRNA maturation to promote HCC progression

Abstract Ubiquitin-specific protease 39(USP39) plays an important role in modulating pre-mRNA splicing and ubiquitin-proteasome dependent proteolysis as a member of conserved deubiquitylation family. Accumulating evidences prove that USP39 participates in the development of hepatocellular carcinoma (HCC). However, little is known about the mechanism especially deubiquitinating target of USP39 in regulating hepatocellular carcinoma (HCC) growth. Here, we prove that USP39 promotes HCC cell proliferation and migration by directly deubiquitin β-catenin, a key molecular of Wnt/β-catenin signaling pathway whose abnormal expression or activation results in several tumors, following its co-localization with USP39. In this process, the expression of E3 ligase TRIM26, which is proved to restrain HCC in our previous research, shows a decreasing trend. We further demonstrate that TRIM26 pre-mRNA splicing and maturation is inhibited by USP39, accompanied by its reduction of ubiquitinating β-catenin, facilitating HCC progression indirectly. In summary, our data reveal a novel mechanism in the progress of HCC that USP39 promotes the proliferation and migration of HCC through increasing β-catenin level via both direct deubiquitination and reducing TRIM26 pre-mRNA maturation and splicing, which may provide a new idea and target for clinical treatment of HCC.