Methylation of Polycomb Target Genes in Intestinal Cancer Is Mediated by Inflammation
- 15 December 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (24), 10280-10289
- https://doi.org/10.1158/0008-5472.can-08-1957
Abstract
Epigenetic changes are strongly associated with cancer development. DNA hypermethylation is associated with gene silencing and is often observed in CpG islands. Recently, it was suggested that aberrant CpG island methylation in tumors is directed by Polycomb (PcG) proteins. However, specific mechanisms responsible for methylation of PcG target genes in cancer are not known. Chronic infection and inflammation contribute to up to 25% of all cancers worldwide. Using glutathione peroxidase, Gpx1 and Gpx2, double knockout (Gpx1/2-KO) mice as a model of inflammatory bowel disease predisposing to intestinal cancer, we analyzed genome-wide DNA methylation in the mouse ileum during chronic inflammation, aging, and cancer. We found that inflammation leads to aberrant DNA methylation in PcG target genes, with 70% of the ∼250 genes methylated in the inflamed tissue being PcG targets in embryonic stem cells and 59% of the methylated genes being marked by H3K27 trimethylation in the ileum of adult wild-type mice. Acquisition of DNA methylation at CpG islands in the ileum of Gpx1/2-KO mice frequently correlates with loss of H3K27 trimethylation at the same loci. Inflammation-associated DNA methylation occurs preferentially in tissue-specific silent genes and, importantly, is much more frequently represented in tumors than is age-dependent DNA methylation. Sixty percent of aberrant methylation found in tumors is also present in the inflamed tissue. In summary, inflammation creates a signature of aberrant DNA methylation, which is observed later in the malignant tissue and is directed by the PcG complex. [Cancer Res 2008;68(24):10280–9]Keywords
Other Versions
This publication has 49 references indexed in Scilit:
- High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancerProceedings of the National Academy of Sciences of the United States of America, 2008
- Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assayProceedings of the National Academy of Sciences of the United States of America, 2007
- The Epigenomics of CancerCell, 2007
- A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencingNature Genetics, 2007
- A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem CellsCell, 2006
- Polycomb complexes repress developmental regulators in murine embryonic stem cellsNature, 2006
- Control of Developmental Regulators by Polycomb in Human Embryonic Stem CellsCell, 2006
- SUZ12 Is Required for Both the Histone Methyltransferase Activity and the Silencing Function of the EED-EZH2 ComplexMolecular Cell, 2004
- Drosophila Enhancer of Zeste/ESC Complexes Have a Histone H3 Methyltransferase Activity that Marks Chromosomal Polycomb SitesCell, 2002
- Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colonNature Genetics, 1994