Abstract 5739: Targeting EZH2 histone methyltransferase activity alleviates inflammatory bowel disease

Abstract

Abstract Objective: Inflammation plays crucial roles in the pathogenesis of inflammatory bowel disease (IBD). Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27m3) is critical to immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during IBD. This study aimed to explore the effects of targeting EZH2 methyltransferase activity on IBD progression in mice. Design: EZH2's enzymatic activity inhibitor GSK343 or GSK126 were delivered by intravenous injection to C57BL/6 mice at the onset, or during the ongoing of IBD, induced by dextran sodium sulfate (DSS). Azoxymethane (AOM)/DSS protocol was applied to trigger colitis-associated colorectal cancer (CAC). Immune cells in the colon of colitis mice were analyzed by flow cytometry, immunofluorescence staining and myeloid-derived suppressor cells (MDSCs) deletion experiments. We differentiated mouse hematopoietic progenitor cells (HPCs) into MDSCs in vitro to investigate the effect of GSK343 on MDSCs generation. Results: Inhibition of EZH2 activity significantly attenuated IBD-related symptoms and inflammation, substantially delaying the onset of CAC. Injection of GSK343 increased the number of functional MDSCs in the colons during IBD. Deletion of MDSCs abrogated the protective effects of GSK343 on IBD. Moreover, inhibition of EZH2 activity promoted the generation of MDSCs from HPCs. Conclusion: Inhibition of EZH2 activity alleviates DSS-induced colitis by promoting MDSC development, and might serve as a new therapeutic strategy to treat IBD. Additionally, EZH2 inhibition enhances MDSC generation, therefore, EZH2 enzymatic inhibitors now in clinical trials for cancer treatment may hinder beneficial anticancer immunity responses. Citation Format: Haixia Long, Jie Zhou, Zhongyu Wang, Shuo Huang, Bo Zhu. Targeting EZH2 histone methyltransferase activity alleviates inflammatory bowel disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5739.