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The Wnt–β-catenin pathway is aberrantly activated in most colon cancers.DICKKOPF-1(DKK-1) gene encodes an extracellular Wnt inhibitor that blocks the formation of signalling receptor complexes at the plasma membrane. We report that 1α,25-dihydroxyvitamin D3[1,25(OH)2D3], the most active vitamin D metabolite, increases the level ofDKK-1RNA and protein in human SW480-ADH colon cancer cells. This effect is dose dependent, slow and depends on the presence of a transcription-competent nuclear vitamin D receptor (VDR). Accordingly, 1,25(OH)2D3activates a 2300 bp fragment of the humanDKK-1gene promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)2D3treatment induced a pattern of histone modifications which is compatible with transcriptionally active chromatin.DKK-1is expressed at high level in colon cancer cell lines with a differentiated phenotype such as Caco-2 or HT-29. Exogenous expression of E-cadherin into SW480-ADH cells results in a strong adhesive phenotype and a 17-fold increase inDKK-1RNA. In contrast, an E-cadherin blocking antibody inhibits 1,25(OH)2D3-induced differentiation of SW480-ADH cells andDKK-1gene expression. Remarkably,in vivotreatment with the vitamin D analogue EB1089 induced DKK-1 protein expression in SW480-ADH cells xenografted in immunodeficient mice, and a correlation was observed in the expression ofVDRandDKK-1RNA in a series of 32 human colorectal tumours. These data indicate that 1,25(OH)2D3activates the transcription of theDKK-1gene, probably in an indirect way that is associated to the promotion of a differentiated phenotype.DKK-1gene induction constitutes a novel mechanism of inhibition of Wnt signalling and antitumour action by 1,25(OH)2D3.

carcinogenesis

The Wnt antagonist               DICKKOPF-1               gene is induced by 1α,25-dihydroxyvitamin D              3               associated to the differentiation of human colon cancer cells