Ubiquitin specific protease 4 positively regulates the WNT/β-catenin signaling in colorectal cancer

beta-catenin is a key signal transducer in the canonical WNT pathway and is negatively regulated by ubiquitin-dependent proteolysis. Through screening of various deubiquitinating enzymes (DUBS), we identified ubiquitin specific protease 4 (USP4) as a candidate for beta-catenin-specific DUB. The effects of USP4 overexpression or knockdown suggested that USP4 positively controls the stability of beta-catenin and enhances beta-catenin-regulated transcription. Domain mapping results revealed that the C-terminal catalytic domain is responsible for beta-catenin binding and nuclear transport. Examination of colon cancer tissues from patients revealed a correlation between elevated expression levels of USP4 and beta-catenin. Consistent with this correlation, USP4 knockdown in HCT116, a colon cancer cell line, reduced invasion and migration activity. These observations indicate that USP4 acts as a positive regulator of the WNT/beta-catenin pathway by deubiquitination and facilitates nuclear localization of beta-catenin. Therefore, we propose that USP4 is a potential target for anti-cancer therapeutics. (c) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.