DIF-1 inhibits the Wnt/β-catenin signaling pathway by inhibiting TCF7L2 expression in colon cancer cell lines

Kentaro Jingushi, Fumi Takahashi-Yanaga, Tatsuya Yoshihara, Fumie Shiraishi, Yutaka Watanabe, Masato Hirata, Sachio Morimoto, Toshiyuki Sasaguri

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

We previously reported that differentiation-inducing factor-1 (DIF-1), a morphogen in Dictyostelium discoideum, inhibits the proliferation of human cancer cell lines by inducing β-catenin degradation and suppressing the Wnt/β-catenin signaling pathway. To determine whether β-catenin degradation is essential for the effect of DIF-1, we examined the effect of DIF-1 on human colon cancer cell lines (HCT-116, SW-620 and DLD-1), in which the Wnt/β-catenin signaling pathway is constitutively active. DIF-1 strongly inhibited cell proliferation and arrested the cell cycle in the G 0/G 1 phase via the suppression of cyclin D1 expression at mRNA and protein levels without reducing β-catenin protein. TCF-dependent transcriptional activity and cyclin D1 promoter activity were revealed to be inhibited via suppression of transcription factor 7-like 2 (TCF7L2) expression. Luciferase reporter assays and EMSAs using the TCF7L2 promoter fragments indicated that the binding site for the transcription factor early growth response-1 (Egr-1), which is located in the-609 to-601 bp region relative to the start codon in the TCF7L2 promoter, was involved in DIF-1 activity. Moreover, RNAi-mediated depletion of endogenous TCF7L2 resulted in reduced cyclin D1 promoter activity and protein expression, and the overexpression of TCF7L2 overrode the inhibition of the TCF-dependent transcriptional activity and cyclin D1 promoter activity induced by DIF-1. Therefore, DIF-1 seemed to inhibit the Wnt/β-catenin signaling pathway by suppressing TCF7L2 expression via reduced Egr-1-dependent transcriptional activity in these colon cancer cell lines. Our results provide a novel insight into the mechanisms by which DIF-1 inhibits the Wnt/β-catenin signaling pathway.

Original languageEnglish
Pages (from-to)47-56
Number of pages10
JournalBiochemical Pharmacology
Volume83
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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