title: DIF-1 inhibits the Wnt/β-catenin signaling pathway by inhibiting TCF7L2 expression in colon cancer cell lines.
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.
authors: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Kentaro
authors: K
authors: Jingushi
authors: Fumi
authors: F
authors: Takahashi-Yanaga
authors: Tatsuya
authors: T
authors: Yoshihara
authors: Fumie
authors: F
authors: Shiraishi
authors: Yutaka
authors: Y
authors: Watanabe
authors: Masato
authors: M
authors: Hirata
authors: Sachio
authors: S
authors: Morimoto
authors: Toshiyuki
authors: T
authors: Sasaguri
mesh_terms: D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D058118:Transcription Factor 7-Like 2 Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D006588:Hexanones; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; C053433:1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone