Activation of CTNNB1 by deubiquitinase UCHL3 mediated stabilization facilitates bladder cancer progression

Abstract

Abstract The catenin beta 1 gene (CTNNB1) plays a crucial role in the malignant progression of various cancers. Emerging studies have suggested that its hyperactivation is closely related to the occurrence and development of bladder cancer(BCa). Here, we report that UCHL3(Ubiquitin C-terminal hydrolase L3), a deubiquitinating enzyme promotes the development of bladder cancer through Wnt signaling pathway by interacting with and stabilizing CTNNB1 in vitro and in vivo. GSEA analysis showed that UCHL3 was highly associated with Wnt signaling pathway, and it was validated by luciferase reporter assays and RT-PCR, which found that its functions depend on its deubiquitinating activity. We also found that the overexpression of UCHL3 boosted the bladder cancer cells proliferation, invasion and migration, while the depletion of UCHL3 in bladder cancer cells delayed the tumor tumorigenesis in vitro and in vivo. Especially, Uchl3-deficient mice were less susceptible to bladder tumorigenesis. Additionally, UCHL3 was highly expressed in bladder cancer and associated with advanced clinicopathological parameters. These findings provided direct insight into the molecular mechanism of the functions of UCHL3 in bladder cancer, and provided new target for therapeutic approach against bladder cancer.