The Wnt antagonist DICKKOPF-1 gene is induced by 1α,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells

• Published in: Carcinogenesis (New York) 2007-09, Vol.28 (9), p.1877-1884
• Main Authors: Aguilera, Oscar, Peña, Cristina, García, José Miguel, Larriba, María Jesús, Ordóñez-Morán, Paloma, Navarro, Diego, Barbáchano, Antonio, López de Silanes, Isabel, Ballestar, Esteban, Fraga, Mario F., Esteller, Manel, Gamallo, Carlos, Bonilla, Félix, González-Sancho, José Manuel, Muñoz, Alberto
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Gastroenterology. Liver. Pancreas. Abdomen; Medical sciences; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgm094

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.