title: Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions.
abstract: Dysregulation of canonical Wnt signaling is thought to play a role in colon carcinogenesis. β-Catenin, a key mediator of the pathway, is stabilized upon Wnt activation and accumulates in the nucleus, where it can interact with the transcription factor T cell factor (TCF) to transactivate gene expression. Normal colonic epithelia express a truncated TCF-1 form, called dnTCF-1, that lacks the critical β-catenin-binding domain and behaves as a transcriptional suppressor. How the cell maintains a balance between the two forms of TCF-1 is unclear. Here, we show that ERM-binding phosphoprotein 50 (EBP50) modulates the interaction between β-catenin and TCF-1. We observed EBP50 localization to the nucleus of human colorectal carcinoma cell lines at low cell culture densities and human primary colorectal tumors that manifested a poor clinical outcome. In contrast, EBP50 was primarily membranous in confluent cell lines. Aberrantly located EBP50 stabilized conventional β-catenin/TCF-1 complexes and connected β-catenin to dnTCF-1 to form a ternary molecular complex that enhanced Wnt/β-catenin signaling events, including the transcription of downstream oncogenes such as c-Myc and cyclin D1. Genome-wide analysis of the EBP50 occupancy pattern revealed consensus binding motifs bearing similarity to Wnt-responsive element. Conventional chromatin immunoprecipitation assays confirmed that EBP50 bound to genomic regions highly enriched with TCF/LEF binding motifs. Knockdown of EBP50 in human colorectal carcinoma cell lines compromised cell cycle progression, anchorage-independent growth, and tumorigenesis in nude mice. We therefore suggest that nuclear EBP50 facilitates colon tumorigenesis by modulating the interaction between β-catenin and TCF-1.
authors.affiliation: Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Lin
authors.forename: Yung-Ho
authors.initials: YH
authors.lastname: Hsu
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Huang
authors.forename: Yih-Jyh
authors.initials: YJ
authors.lastname: Shann
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.forename: Chi-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Tzuu-Shuh
authors.initials: TS
authors.lastname: Jou
mesh_terms: D021581:Active Transport, Cell Nucleus; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D054731:PDZ Domains; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051822:T Cell Transcription Factor 1 / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D051822:T Cell Transcription Factor 1; D051176:beta Catenin; C093376:sodium-hydrogen exchanger regulatory factor