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

• Published in: Oncogene Vol. 25; no. 29; pp. 4116 - 4121
• Main Authors: Aguilera, O, Fraga, M F, Ballestar, E, Paz, M F, Herranz, M, Espada, J, García, J M, Muñoz, A, Esteller, M, González-Sancho, J M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 06.07.2006
• Subjects: Adaptor Proteins, Signal Transducing; Adenomatous polyposis coli; Adenomatous polyposis coli protein; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Animals; Antimetabolites, Antineoplastic - pharmacology; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Carrier Proteins - genetics; Carrier Proteins - secretion; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Colon - metabolism; Colon - pathology; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CpG islands; CpG Islands - genetics; Dkk1 protein; DNA Methylation; Epigenesis, Genetic; Epigenetics; Epithelium - metabolism; Epithelium - pathology; Frizzled protein; Frizzled-related protein 1; Genes; Genes, Tumor Suppressor; Humans; Inhibitor drugs; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Lymphocytes T; Mice; Mice, Nude; Neoplasia; Neoplasm Transplantation; Oncology; Polyposis coli; Promoter Regions, Genetic - genetics; Repressor Proteins - genetics; Repressor Proteins - secretion; Rodents; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Transcription factors; Transplantation, Heterologous; Tumor cell lines; Tumor suppressor genes; Tumorigenesis; Tumors; Wnt protein; Wnt Proteins - antagonists & inhibitors; Wnt Proteins - genetics; Wnt Proteins - metabolism; β-Catenin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209439

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).