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

ABSTRACT: ?-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 ?-catenin-specific DUB. The effects of USP4 overexpression or knockdown suggested that USP4 positively controls the stability of ?-catenin and enhances ?-catenin-regulated transcription. Domain mapping results revealed that the C-terminal catalytic domain is responsible for ?-catenin binding and nuclear transport. Examination of colon cancer tissues from patients revealed a correlation between elevated expression levels of USP4 and ?-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/?-catenin pathway by deubiquitination and facilitates nuclear localization of ?-catenin. Therefore, we propose that USP4 is a potential target for anti-cancer therapeutics.

SUBMITTER: Yun SI 

PROVIDER: S-EPMC5528720 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature