title: DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer.
abstract: The gene encoding 'deleted in breast cancer 2' (DBC2), also referred to as RHOBTB2 (Rho-related BTB domain-containing protein 2), is classified as a tumor suppressor gene. DBC2 is a substrate-specific adaptor protein for a novel class of Cullin-3 (CUL3)-based E3 ubiquitin ligases; however, it is unclear if the substrate adaptor function of DBC2 is required for its tumor suppressor activity. Furthermore, the key substrates of DBC2-mediated ubiquitination have yet to be identified. In the present study, we established a genome-wide human cDNA library-based in vitro ubiquitination target screening assay and identified Musashi-2 (MSI2) as a novel ubiquitination target protein of DBC2. MSI2 directly interacted with DBC2, and this interaction promoted MSI2 polyubiquitination and proteasomal degradation in breast cancer cells. Overexpression and knockdown experiments demonstrated that DBC2 suppressed MSI2-associated oncogenic functions and induced apoptosis. Immunohistochemistry analysis of a breast cancer tissue microarray revealed that DBC2 and MSI2 protein levels are inversely correlated in both normal breast tissues and breast cancer tissues. Taken together, these findings provide evidence that DBC2 suppresses tumorigenesis in breast cancer by ubiquitinating MSI2.
authors.affiliation: KU Center for Integrated Science and Technology, Konkuk University, Seoul, South Korea.|Korea Institute of Dermatological Sciences, 2nd Enterprise Research Building, Chungcheongbuk-do, South Korea.
authors.forename: Y M
authors.initials: YM
authors.lastname: Choi
authors.affiliation: Korea Institute of Dermatological Sciences, 2nd Enterprise Research Building, Chungcheongbuk-do, South Korea.
authors.forename: K B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Oncology, Cheil General Hospital and Women's Healthcare Center, Dankook University, College of Medicine, Seoul, South Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Cheil General Hospital and Women's Healthcare Center, Dankook University, College of Medicine, Seoul, South Korea.
authors.forename: Y K
authors.initials: YK
authors.lastname: Chun
authors.affiliation: Korea Institute of Dermatological Sciences, 2nd Enterprise Research Building, Chungcheongbuk-do, South Korea.
authors.forename: I S
authors.initials: IS
authors.lastname: An
authors.affiliation: KU Center for Integrated Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: S
authors.initials: S
authors.lastname: An
authors.affiliation: KU Center for Integrated Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: S
authors.initials: S
authors.lastname: Bae
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D014408:Biomarkers, Tumor; C438151:MSI2 protein, human; C497336:RHOBTB2 protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins