title: Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate beta-catenin activity in colon cancer cells.
abstract: The activity of beta-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 D(3) (1,25D) and pro-tumorigenic lithocholic acid (LCA) VDR ligands on beta-catenin transcriptional activity. Furthermore, the influence of a major regulatory protein of beta-catenin, the APC tumor suppressor gene, on VDR-dependent inhibition of beta-catenin activity was examined. We report herein that beta-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 beta-catenin transcriptional activity, though 1,25D exhibited significantly greater inhibition. Moreover, 1,25D, but not LCA, suppressed endogenous expression of the beta-catenin target gene DKK-4 independent of VDR DNA-binding activity. These results support beta-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 beta-catenin activity by 1,25D-VDR was significantly enhanced by wild-type APC. These results reveal a previously unrecognized role for 1,25D-VDR in APC/beta-catenin cross talk. Collectively, these findings strengthen evidence favoring a direct effect on the Wnt-signaling molecule beta-catenin as one anti-cancer target of 1,25D-VDR action in the colorectum.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Egan
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Milen V
authors.initials: MV
authors.lastname: Vitanov
authors.forename: Leonid
authors.initials: L
authors.lastname: Bartik
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Jacobs
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Gerner
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D018938:Caco-2 Cells; D002117:Calcitriol / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008095:Lithocholic Acid / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C442333:DKK4 protein, human; D003902:Detergents; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D008095:Lithocholic Acid; D002117:Calcitriol