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/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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism
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Animals
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Antimetabolites, Antineoplastic / pharmacology
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Azacitidine / analogs & derivatives
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Azacitidine / pharmacology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Colon / metabolism
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Colon / pathology
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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CpG Islands / genetics
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DNA Methylation
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Decitabine
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Epigenesis, Genetic*
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Epithelium / metabolism
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Epithelium / pathology
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Genes, Tumor Suppressor*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Promoter Regions, Genetic / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transplantation, Heterologous
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Wnt Proteins / antagonists & inhibitors
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Wnt Proteins / genetics*
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Wnt Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein
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Antimetabolites, Antineoplastic
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Carrier Proteins
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DKK1 protein, human
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Intercellular Signaling Peptides and Proteins
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Repressor Proteins
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WIF1 protein, human
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Wnt Proteins
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Decitabine
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Azacitidine