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

• Ubiquitin specific protease 4 (USP4) positively regulates WNT/β-catenin signaling.
• USP4 deubiquitinates β-catenin and increases the stability of β-catenin.
• USP4 level is correlated with β-catenin in colon cancer tissues.
• USP4 is a potential target for anti-cancer treatments.

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

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