DICKKOPF-4 is induced by TCF/[beta]-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1[alpha],25-dihydroxyvitamin D3.
Pendas-Francol, N 1; Garcia, J M 2; Pena, C 2; Valle, N 1; Palmer, H G 3; Heinaniemi, M 4; Carlberg, C 4; Jimenez, B 1,5; Bonilla, F 2; Munoz, A 1; Gonzalez-Sancho, J M 1,5
[Article] Oncogene. 27(32):4467-4477, July 24, 2008.

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Aberrant activation of the Wnt/[beta]-catenin signaling pathway is a hallmark of colon cancer. We show that the Wnt antagonist DICKKOPF-4 (DKK-4) gene is repressed by 1[alpha],25-dihydroxyvitamin D3 (1,25(OH)2D3) in human colon cancer cells. This effect correlated with the inhibition of the DKK-4 promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)2D3 induces early and transient binding of the vitamin D receptor (VDR) and the SMRT corepressor to the region adjacent to the transcription start site of DKK-4. Additionally, we demonstrate that the DKK-4 gene is a new downstream target of TCF/[beta]-catenin. Remarkably, expression of DKK-4 messenger RNA (mRNA) was not detected in a series of 29 human normal (N) colon biopsies but expression was upregulated in all the matched tumour (T) tissues. An inverse correlation existed between the expression of DKK-4 and VDR RNA in the Ts. Ectopic DKK-4 expression increased the migration and invasion properties of colon cancer cells and conditioned media (CM) from DKK-4-expressing cells enhanced the capacity to migrate and form capillary-like tubules of human primary microvascular endothelial cells. In conclusion, DKK-4 is upregulated in colon cancer and is associated with the acquisition of malignant properties by neoplastic cells. DKK-4 downregulation is a novel effect of 1,25(OH)2D3 that may contribute to its anticancer action.

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