Carcinogenesis Advance Access published online on April 21, 2007
Carcinogenesis, doi:10.1093/carcin/bgm094
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The Wnt antagonist DICKKOPF-1 gene is induced by 1
,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells
Instituto de Investigaciones Biomédicas ‘Alberto Sols’ and Departamento de Bioquímica, Facultad de Medicina, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Spain
1 Hospital Universitario Puerta de Hierro, Madrid, Spain
2 Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
3 Hospital Universitario de la Princesa, Madrid, Spain
* To whom correspondence should be addressed at: Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Arturo Duperier, 4, 28029 Madrid, Spain. Tel: +34 91 585 4451; Fax: +34 91 585 4401. E-mail: amunoz{at}iib.uam.es.
The Wnt/ß-catenin pathway is aberrantly activated in most colon cancers. DICKKOPF-1 (DKK-1) gene encodes an extracellular Wnt inhibitor that blocks the formation of signaling receptor complexes at the plasma membrane. We report that 1
,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 2,300 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 signaling and anti-tumour action by 1,25(OH)2D3.
Key Words: DICKKOPF-1 • Wnt • vitamin D • colon cancer
Received November 30, 2006; revised April 4, 2007; accepted April 9, 2007.
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