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

• Published in: Molecular oncology 2015-11, Vol.9 (9), p.1834-1851
• Main Authors: Yun, Sun-Il, Kim, Hyeon Ho, Yoon, Jung Hwan, Park, Won Sang, Hahn, Myong-Joon, Kim, Hee Cheol, Chung, Chin Ha, Kim, Kyeong Kyu
• Format: Article
• Language: English
• Subjects: beta Catenin - metabolism; Cancer; Catenin; Cell growth; Cell Movement; Colon - metabolism; Colon - pathology; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Embryos; Enzymes; HCT116 Cells; Humans; Kinases; Localization; Mutation; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Nuclear transport; Pathogenesis; Proteinase; Proteins; Proteolysis; Rectum - metabolism; Rectum - pathology; RNA Interference; RNA, Small Interfering - genetics; Stem cells; Transcription; Ubiquitin; Ubiquitin specific protease 4 (USP4); Ubiquitin Thiolesterase - analysis; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin-Specific Proteases; Ubiquitination; Wnt protein; Wnt Proteins - metabolism; Wnt Signaling Pathway; β-catenin
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2015.06.006

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. [Display omitted] •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.