Methylation of Polycomb Target Genes in Intestinal Cancer Is Mediated by Inflammation

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 proteins. However, specific mechanisms responsible for methylation of Polycomb 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 Polycomb (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 wildtype mice. Acquisition of DNA methylation at CpG islands in the ileum of Gpx-1/2-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. 60% 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.

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

“…Using glutathione peroxidase Gpx1 and Gpx2 doubleknockout (Gpx1/2-KO) mice, genome-wide DNA methylation studies of tumors and pre-cancerous lesions demonstrated a limited number of loci with moderate degree of promoter CpG DNA methylation. 35 This result, along with our findings in spontaneously immortalized mouse fibroblasts, suggests that the molecular machinery responsible for promoter CpG island DNA hypermethylation is present in mouse cells, but this global epigenetic event is not initiated nor required for tumorigenesis in GEMMs driven by an oncogene, at least not in the five GEMMs we examined. Cancer arising from inflammatory states, however, may require the initiation of global epigenetic dysregulation in pre-neoplastic tissues to allow for the selection of clones that harbor the prerequisite epigenetic and genetic changes found in a malignant cell.…”

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

“…IL-32 is known to promote apoptosis of keratinocytes in atopic dermatitis (11), which supports our results that identified an apoptosis regulator, DAPK-1, as a protein target for IL-32. Another study has shown that inflammation can lead to aberrant DNA methylation of the DAPK-1 gene in a model of IBD (40). In addition, DAPK has been recently described as a potential therapeutic target for chronic neurodegenerative diseases (41).…”

Epigenetic Mechanisms in Inflammation

“…It was reported recently that some of these targets are subject to aberrant DNA methylation following chronic inflammation (Hahn et al, 2008). It was shown that PcG proteins bind to the regulatory regions of target genes and recruit DNMTs (Fig.…”