Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate β-catenin activity in colon cancer cells

Jan B. Egan, Patricia A. Thompson, Milen V. Vitanov, Leonid Bartik, Elizabeth T. Jacobs, Mark R. Haussler, Eugene W. Gerner, Peter Jurutka

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

The activity of β-catenin, commonly dysregulated in human colon cancers, is inhibited by the vitamin D receptor (VDR), and this mechanism is postulated to explain the putative anti-cancer activity of vitamin D metabolites in the colon. We investigated the effect of a common FokI restriction site polymorphism (F/f) in the human VDR gene as well as the effect of anti-tumorigenic 1,25-dihydroxyvitamin D3 (1,25D) and pro-tumorigenic lithocholic acid (LCA) VDR ligands on β-catenin transcriptional activity. Furthermore, the influence of a major regulatory protein of β-catenin, the APC tumor suppressor gene, on VDR-dependent inhibition of β-catenin activity was examined. We report herein that β-catenin-mediated transcription is most effectively suppressed by the VDR FokI variant F/M4 when 1,25D is limiting. Using Caco-2 colorectal cancer (CRC) cells, it was observed that VDR ligands, 1,25D and LCA, both suppress β-catenin transcriptional activity, though 1,25D exhibited significantly greater inhibition. Moreover, 1,25D, but not LCA, suppressed endogenous expression of the β-catenin target gene DKK-4 independent of VDR DNA-binding activity. These results support β-catenin sequestration away from endogenous gene targets by 1,25D-VDR. This activity is most efficiently mediated by the FokI gene variant F/M4, a VDR allele previously associated with protection against CRC. Interestingly, we found the inhibition of β-catenin activity by 1,25D-VDR was significantly enhanced by wildtype APC. These results reveal a previously unrecognized role for 1,25D-VDR in APC/β-catenin cross talk. Collectively, these findings strengthen evidence favoring a direct effect on the Wnt-signaling molecule β-catenin as one anti-cancer target of 1,25D-VDR action in the colorectum.

Original languageEnglish (US)
Pages (from-to)337-352
Number of pages16
JournalMolecular Carcinogenesis
Volume49
Issue number4
DOIs
StatePublished - Apr 1 2010

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Keywords

  • 1,25-dihydroxyvitamin D
  • Colorectal cancer
  • Lithocholic acid
  • Single nucleotide polymorphisms
  • Wnt signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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