Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and beta-catenin interactions
Resource
J. Clin. Invest., 122(5), 1881-1894
Journal
J. Clin. Invest.
Journal Volume
122
Journal Issue
5
Pages
1881-1894
Date Issued
2012
Date
2012
Author(s)
Lin, Yu-Yu
Hsu, Yung-Ho
Huang, Hsin-Yi
Shann, Yih-Jyh
Huang, Chi-Ying F.
Wei, Shu-Chen
Chen, Chi-Ling
Jou, Tzuu-Shuh
Abstract
Dysregulation of canonical Wnt signaling is thought to play a role in colon carcinogenesis. beta-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 beta-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 ERNI-binding phosphoprotein 50 (EBP50) modulates the interaction between beta-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 beta-catenin/TCF-1 complexes and connected beta-catenin to dnTCF-1 to form a ternary molecular complex that enhanced Wnt/beta-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 beta-catenin and TCF-1.
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