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

Oncogene. 2006 Jul 6;25(29):4116-21. doi: 10.1038/sj.onc.1209439. Epub 2006 Feb 20.


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/beta-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 beta-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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Colon / metabolism
  • Colon / pathology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • CpG Islands / genetics
  • DNA Methylation
  • Decitabine
  • Epigenesis, Genetic*
  • Epithelium / metabolism
  • Epithelium / pathology
  • Genes, Tumor Suppressor*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Promoter Regions, Genetic / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transplantation, Heterologous
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / genetics*
  • Wnt Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • Antimetabolites, Antineoplastic
  • Carrier Proteins
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Repressor Proteins
  • WIF1 protein, human
  • Wnt Proteins
  • Decitabine
  • Azacitidine