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Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer

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Abstract

Colorectal cancer is a major cause of cancer death worldwide. A number of key oncogenes and tumor suppressor genes have been proposed to drive progression from healthy colonic epithelia to malignant tumors, including members of the Wnt/β-catenin pathway. Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1). Here, we show for the first time that another extracellular Wnt inhibitor, the DICKKOPF-1 (DKK-1) gene, is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines (n=9), whereas treatment with the DNA-demethylating agent 5-aza-2-deoxycytidine restored DKK-1 expression. Restoration of DKK-1 function in non-expressing cells bearing a truncated APC (Adenomatous Polyposis Coli) gene had no effect on β-catenin/T-cell factor-dependent transcription, but induced tumor suppressor-like features such as reduced colony formation density and tumor growth inhibition in nude mice. These results suggest additional functions for DKK-1 other than inhibiting canonical Wnt signaling. In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases. Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors).

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Acknowledgements

We thank Esteban Fernando Setién, Paula García, Sara Casado and Diego Navarro for excellent technical assistance. Grant support: Ministerio de Educación y Ciencia (SAF2004-01015) of Spain, Fundación de Investigación Médica Mutua Madrileña.

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Author notes

  1. O Aguilera and M F Fraga: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’ and Departamento de Bioquímica, Facultad de Medicina, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid, Spain

    O Aguilera, A Muñoz & J M González-Sancho

  2. Molecular Pathology Programme, Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid, Spain

    M F Fraga, E Ballestar, M F Paz, M Herranz, J Espada & M Esteller

  3. Hospital Universitario Puerta de Hierro, Madrid, Spain

    J M García

Authors
  1. O Aguilera
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  2. M F Fraga
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  3. E Ballestar
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  4. M F Paz
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  5. M Herranz
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  6. J Espada
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  7. J M García
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  8. A Muñoz
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  9. M Esteller
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  10. J M González-Sancho
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Corresponding author

Correspondence to M Esteller.

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Aguilera, O., Fraga, M., Ballestar, E. et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25, 4116–4121 (2006). https://doi.org/10.1038/sj.onc.1209439

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  • DOI: https://doi.org/10.1038/sj.onc.1209439

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