title: Ubiquitin specific protease 4 positively regulates the WNT/β-catenin signaling in colorectal cancer.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Sun-Il
authors.initials: SI
authors.lastname: Yun
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Seoul 135-710, South Korea; Samsung Biomedical Research Institute, Samsung Medical Center, Seoul 135-710, South Korea.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea.
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Myong-Joon
authors.initials: MJ
authors.lastname: Hahn
authors.affiliation: Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Seoul 135-710, South Korea; Samsung Biomedical Research Institute, Samsung Medical Center, Seoul 135-710, South Korea. Electronic address: kyeongkyu@skku.edu.
authors.forename: Kyeong Kyu
authors.initials: KK
authors.lastname: Kim
mesh_terms: D002465:Cell Movement; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045325:HCT116 Cells; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012007:Rectum / Q000378:metabolism / Q000473:pathology*; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C486203:USP4 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
keywords: Cancer; Ubiquitin specific protease 4 (USP4); β-catenin