Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions
Journal
Journal of Clinical Investigation
Journal Volume
122
Journal Issue
5
Pages
1881-1894
Date Issued
2012
Author(s)
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.
SDGs
Other Subjects
beta catenin; cyclin D1; ERM binding phosphoprotein 50; phosphoprotein; transcription factor 7; unclassified drug; Wnt protein; anchorage independent growth; animal experiment; animal model; animal tissue; article; cancer survival; carcinoma cell; cell cycle progression; cell density; cell nucleus; cell proliferation; chromatin immunoprecipitation; colon carcinogenesis; colorectal cancer; colorectal carcinogenesis; complex formation; consensus sequence; controlled study; disease specific survival; DNA responsive element; female; genome analysis; human; human cell; major clinical study; male; mouse; nonhuman; nucleotide sequence; oncogene c myc; outcome assessment; overall survival; PDZ domain; priority journal; promoter region; protein binding; protein function; protein motif; protein protein interaction; signal transduction; tumor xenograft; Active Transport, Cell Nucleus; Aged; Aged, 80 and over; Animals; Base Sequence; beta Catenin; Binding Sites; Carcinoma; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; Middle Aged; Multiprotein Complexes; Neoplasm Transplantation; PDZ Domains; Phosphoproteins; Promoter Regions, Genetic; Protein Binding; Signal Transduction; Sodium-Hydrogen Antiporter; T Cell Transcription Factor 1
Type
journal article