Abstract 5349: Aberrant trimethylation of histone H3 lysine 27 is induced by chronic inflammation in mouse colonic epithelial cells, and is involved in the formation of a field for cancerization.

Abstract

Abstract A field for cancerization (field defect), where genetic and epigenetic alterations are accumulated in normal-appearing tissues, is involved in human carcinogenesis, especially cancers associated with chronic inflammation. While aberrant DNA methylation is involved in the field defect and induced by chronic inflammation [Ushijima and Hattori, Clin Cancer Res, 2012], it is still unclear for trimethylation of histone H3 lysine 27 (H3K27me3), which is involved in gene repression independent of DNA methylation and functions as a pre-mark for aberrant DNA methylation. In this study, using a mouse colitis model induced by dextran sulfate sodium (DSS), we aimed to clarify whether or not aberrant H3K27me3 is induced by inflammation and involved in a field defect. Analysis of H3K27me3 levels in colonic epithelial cells by chromatin immunoprecipitation combined with CpG island microarray analysis (ChIP-on-chip analysis) revealed that H3K27me3 levels were increased or decreased for 266 genomic regions by aging, and more extensively (27 increased and 3,782 decreased regions) by colitis. Among the 3,809 regions with alterations by DSS-induced colitis, 212 regions overlapped with those whose alterations were induced by aging. Analysis of the temporal profiles of H3K27me3 levels in the course of DSS treatment revealed that increase or decrease of H3K27me3 was induced as early as two weeks after the initiation of DSS treatment, and persisted at least for 16 weeks, even after the inflammation disappeared. Some of the aberrant H3K27me3 in colonic epithelial cells was carried over into colon tumors. Furthermore, H3K27me3 acquired at Dapk1 by colitis was followed by increased DNA methylation, supporting its function as a pre-mark for aberrant DNA methylation [Takeshima et al., Carcinogenesis, in press]. Regarding mechanisms of aberrant H3K27me3 induction, expression changes of polycomb-related genes including Ezh2, Kdm6a, and Kdm6b, were not involved. These results demonstrated that aberrant H3K27me3 can be induced by exposure to a specific environment, such as colitis, and suggested that aberrant histone modification, in addition to aberrant DNA methylation, is involved in the formation of a field defect. Citation Format: Hideyuki Takeshima, Daigo Ikegami, Mika Wakabayashi, Tohru Niwa, Young-Joon Kim, Toshikazu Ushijima. Aberrant trimethylation of histone H3 lysine 27 is induced by chronic inflammation in mouse colonic epithelial cells, and is involved in the formation of a field for cancerization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5349. doi:10.1158/1538-7445.AM2013-5349