Abstract 2401: Connecting oxidative DNA damage to epigenetic alterations during inflammation-driven tumorigenesis
Authors: Ashley Maiuri, Ning Ding, Heather M. O'Hagan
Journal: Cancer Research (2017)

Abstract Inflammation contributes to the development of a diverse array of diseases, including cancer. At sites of chronic inflammation epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation initiates epigenetic alterations. Cancer cells are globally DNA hypomethylated, but have aberrant gains in promoter DNA methylation that transcriptionally silence tumor suppressor genes (TSGs), linking DNA methylation directly to tumorigenesis. However, the mechanisms of targeting and initiation for these stable disease-specific epigenetic marks are unknown. We have linked inflammation and oxidative DNA damage to acute changes in the interaction of epigenetic silencing proteins with each other and the chromatin. Recently, we demonstrated that the mismatch repair (MMR) protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin and provided evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription. To connect these findings to epigenetic changes in tumors we use a model of inflammation-driven tumorigenesis where we infect mice with the human commensal bacterium enterotoxigenic Bacteriodes fragilis (ETBF). ETBF infection causes colon inflammation that drives tumorigenesis in Multiple intestinal neoplasia (Min) mice. The central hypothesis for this work is that oxidative damage at sites of inflammation causes acute genome-wide changes in the binding of epigenetic silencing proteins that result in the permanent epigenetic silencing of genes in tumors that form at the sites of exposure. Using genome-wide DNA methylation techniques we identified TSGs with increased promoter DNA methylation and decreased expression in tumors from ETBF infected Min mice as compared to normal tissue. In Min mice lacking expression of Msh2 in their intestinal epithelium (Msh2lox/loxVCMin) there is a loss of the inflammation-induced change in binding of epigenetic proteins that occurs in Min mice even though the cytokine response to infection is normal. Because they lack functional MMR, ETBF infection of Msh2lox/loxVCMin mice causes an increase in colon tumor number and these tumors are positive for microsatellite instability, unlike tumors from ETBF infected Min mice. Importantly, DNA hypo- and hypermethylation changes in tumors from Msh2lox/loxVCMin ETBF infected mice are reduced both globally and at promoter CpG islands of candidate TSGs as compared to tumors from Min ETBF infected mice. Altogether, this work suggests a novel mechanism by which oxidative damage induces acute epigenetic changes through the interaction of DNMT1 with MMR proteins and that this acute change drives DNA methylation alterations during tumorigenesis. Citation Format: Ashley Maiuri, Ning Ding, Heather M. O'Hagan. Connecting oxidative DNA damage to epigenetic alterations during inflammation-driven tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2401. doi:10.1158/1538-7445.AM2017-2401