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The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells.
Carcinogenesis. 2007 Sep; 28(9):1877-84.C

Abstract

The Wnt-beta-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 1alpha,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.

Authors+Show Affiliations

Instituto de Investigaciones Biomédicas Alberto Sols, Facultad de Medicina, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17449905

Citation

Aguilera, Oscar, et al. "The Wnt Antagonist DICKKOPF-1 Gene Is Induced By 1alpha,25-dihydroxyvitamin D3 Associated to the Differentiation of Human Colon Cancer Cells." Carcinogenesis, vol. 28, no. 9, 2007, pp. 1877-84.
Aguilera O, Peña C, García JM, et al. The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis. 2007;28(9):1877-84.
Aguilera, O., Peña, C., García, J. M., Larriba, M. J., Ordóñez-Morán, P., Navarro, D., Barbáchano, A., López de Silanes, I., Ballestar, E., Fraga, M. F., Esteller, M., Gamallo, C., Bonilla, F., González-Sancho, J. M., & Muñoz, A. (2007). The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis, 28(9), 1877-84.
Aguilera O, et al. The Wnt Antagonist DICKKOPF-1 Gene Is Induced By 1alpha,25-dihydroxyvitamin D3 Associated to the Differentiation of Human Colon Cancer Cells. Carcinogenesis. 2007;28(9):1877-84. PubMed PMID: 17449905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. AU - Aguilera,Oscar, AU - Peña,Cristina, AU - García,José Miguel, AU - Larriba,María Jesús, AU - Ordóñez-Morán,Paloma, AU - Navarro,Diego, AU - Barbáchano,Antonio, AU - López de Silanes,Isabel, AU - Ballestar,Esteban, AU - Fraga,Mario F, AU - Esteller,Manel, AU - Gamallo,Carlos, AU - Bonilla,Félix, AU - González-Sancho,José Manuel, AU - Muñoz,Alberto, Y1 - 2007/04/21/ PY - 2007/4/24/pubmed PY - 2008/3/15/medline PY - 2007/4/24/entrez SP - 1877 EP - 84 JF - Carcinogenesis JO - Carcinogenesis VL - 28 IS - 9 N2 - The Wnt-beta-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 1alpha,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. SN - 0143-3334 UR - https://www.unboundmedicine.com/medline/citation/17449905/The_Wnt_antagonist_DICKKOPF_1_gene_is_induced_by_1alpha25_dihydroxyvitamin_D3_associated_to_the_differentiation_of_human_colon_cancer_cells_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgm094 DB - PRIME DP - Unbound Medicine ER -