Carcinogenesis Advance Access originally published online on April 21, 2007
Carcinogenesis 2007 28(9):1877-1884; 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, Arturo Duperier, 4, 28029 Madrid, Spain
1 Hospital Universitario Puerta de Hierro, Madrid, Spain
2 Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre, Madrid, Spain
3 Hospital Universitario de la Princesa, Madrid, Spain
* To whom correspondence should be addressed. Tel: +34 91 585 4451; Fax: +34 91 585 4401; Email: amunoz{at}iib.uam.es
Correspondence may also be addressed to J. M. González Sancho Email: jmgonzalez{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 signalling 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 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.
Abbreviations: DKK-1, DICKKOPF; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; LRP, LDL receptor-related protein; PCR, polymerase chain reaction; TCF, T cell factor; VDR, vitamin D receptor
Received November 30, 2006; revised April 4, 2007; accepted April 9, 2007.
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