Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions

Yu Yu Lin, Yung Ho Hsu, Hsin Yi Huang, Yih Jyh Shann, Chi Ying F Huang, Shu Chen Wei, Chi Ling Chen, Tzuu Shuh Jou

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1881-1894
Number of pages14
JournalJournal of Clinical Investigation
Volume122
Issue number5
DOIs
Publication statusPublished - May 1 2012

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Catenins
T Cell Transcription Factor 1
Phosphoproteins
Carcinogenesis
TCF Transcription Factors
Colorectal Neoplasms
Cell Line
Colon
Chromatin Immunoprecipitation
Cyclin D1
Mouse Hnf1a protein
Oncogenes
Nude Mice
Cell Cycle
Transcription Factors
Epithelium
Cell Culture Techniques
Cell Count
Genome
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions. / 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.

In: Journal of Clinical Investigation, Vol. 122, No. 5, 01.05.2012, p. 1881-1894.

Research output: Contribution to journalArticle

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. / Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 5. pp. 1881-1894.
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