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 W. 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 2010

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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