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DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α,25-dihydroxyvitamin D3

Oncogene volume 27, pages 4467–4477 (2008)Cite this article

Abstract

Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colon cancer. We show that the Wnt antagonist DICKKOPF-4 (DKK-4) gene is repressed by 1α,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/β-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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Acknowledgements

We thank Drs R Bouillon, M Verstuyf and JP Van de Velde for the gift of 1,25(OH)2D3, Dr O Aguilera for reagents and discussion, Dr A Aranda for providing K45E-VDR, Dr C Niehrs for wild-type and mutant Kremen2 expression constructs, and D Navarro and T Martínez for their technical assistance. We also thank R Rycroft for his valuable assistance in the preparation of the english manuscript. This study was supported by grants from Ministerio de Educación y Ciencia (SAF2004-01015, SAF2007-60341 and SAF2004-04152), Ministerio de Sanidad y Consumo ISCIII-RETIC (RD06/0020/0009), Fundación de Investigación Médica Mutua Madrileña, Comunidad de Madrid (S-GEN-0266-2006) and the European Union (MRTN-CT-2005-019496, NucSys).

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Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid, Spain

    N Pendás-Franco, N Valle, B Jiménez, A Muñoz & J M González-Sancho

  2. Hospital Universitario Puerta de Hierro, Madrid, Spain

    J M García, C Peña & F Bonilla

  3. Cambridge Research Institute, Cambridge, UK

    H G Pálmer

  4. Life Science Research Unit, University of Luxembourg, Luxembourg

    M Heinäniemi & C Carlberg

  5. Departamento de Bioquímica, Facultad de Medicina–Universidad Autónoma de Madrid, Madrid, Spain

    B Jiménez & J M González-Sancho

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  1. N Pendás-Franco
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  2. J M García
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  11. J M González-Sancho
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Correspondence to A Muñoz.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Pendás-Franco, N., García, J., Peña, C. et al. DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α,25-dihydroxyvitamin D3. Oncogene 27, 4467–4477 (2008). https://doi.org/10.1038/onc.2008.88

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