USP51, an oncogene for pancreatic cancer (PC) cell growth via Wnt/β-catenin pathway

Abstract Background: Currently, targeting ubiquitin-specific protease (USP) is popular in cancer treatment. Aim: To study the roles of USP51, a member of USPs, in human pancreatic cancer (PC) and the underlying mechanism. Method: Expression of USP51 in tumor pancreatic tissue and PC cell lines were assessed. Overall survival rate of PC patients was measured by Kaplan-Meier method. The association between USP51 and β-catenin in PC cells was determined by Co-Immunoprecipitation (Co-IP) and ubiquitination assay. XAV939 was used to inhibit β-catenin. Protein levels of β-catenin and Cyclin D1 were used to assess the mechanism. Result: Herein, we evidenced high levels of USP51 in tumor tissues of PC patients, which predicted a poor survival. Knockdown of USP51 in MiaPaca2 and SW1990 (two PC cells) inhibited proliferation, arrested MiaPaca2 and SW1990 cells at G0/G1 phases, and impaired tumorigenicity of MiaPaca2 in nude mice, demonstrating the anti-cancer effect of siUSP51 in PC. Moreover, Knockdown of USP51 prevented β-catenin and its downstream Cyclin D1, suggesting the blockade of β-catenin pathway in this process. On the contrary, overexpression of USP51 in ASPC1 (one PC cell) resulted in the opposite effect, facilitating the tumorigenesis of PC and the activation of β-catenin pathway, which were significantly reversed by XAV939. Interestingly, USP51 bound to β-catenin and knockdown of USP51 increased β-catenin ubiquitination. Conclusion: USP51 is an oncogene that is upregulated in PC. USP51 acted as a deubiquitinase that favored β-catenin accumulation, then activated Wnt/β-catenin pathway and exerted carcinogenesis in PC.