Journal Article

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

Oscar Aguilera, Cristina Peña, José Miguel García, María Jesús Larriba, Paloma Ordóñez-Morán, Diego Navarro, Antonio Barbáchano, Isabel López de Silanes, Esteban Ballestar, Mario F. Fraga, Manel Esteller, Carlos Gamallo, Félix Bonilla, José Manuel González-Sancho and Alberto Muñoz

in Carcinogenesis

Volume 28, issue 9, pages 1877-1884
Published in print September 2007 | ISSN: 0143-3334
Published online April 2007 | e-ISSN: 1460-2180 | DOI:
The Wnt antagonist DICKKOPF-1 gene is induced by 1α,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells

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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 of DKK-1 RNA 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)2D3 activates a 2300 bp fragment of the human DKK-1 gene promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)2D3 treatment induced a pattern of histone modifications which is compatible with transcriptionally active chromatin. DKK-1 is 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 in DKK-1 RNA. In contrast, an E-cadherin blocking antibody inhibits 1,25(OH)2D3-induced differentiation of SW480-ADH cells and DKK-1 gene expression. Remarkably, in vivo treatment 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 of VDR and DKK-1 RNA in a series of 32 human colorectal tumours. These data indicate that 1,25(OH)2D3 activates the transcription of the DKK-1 gene, probably in an indirect way that is associated to the promotion of a differentiated phenotype. DKK-1 gene induction constitutes a novel mechanism of inhibition of Wnt signalling and antitumour action by 1,25(OH)2D3.

Journal Article.  5425 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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