Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation

Jie Zhou,Yisong Y Wan,Shuo Huang,Qi-Jing Li,Haixia Long,Bo Zhu,Liang Xu,Jiani Huang,Xuefeng Tang,Zhongyu Wang,Alistair L J Symonds

doi:10.1038/s41467-019-10176-2

Abstract

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme’s activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.

Highlights

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation
Using GSK343, a selective EZH2 inhibitor, we demonstrate that the protective role of EZH2 inhibition is associated with increased Myeloid-derived suppressor cells (MDSCs) populations in the colonic lamina propria
The classic signs of colitis, including body weight loss (Fig. 4b), disease activity index (DAI) (Fig. 4c), colon shortening (Fig. 4d), and pathology (Fig. 4e), all worsened in GSK343-treated mice upon anti-Gr-1 antibody administration. These results strongly suggest that the protective effects on colitis of EZH2 methyltransferase inhibition depend on elevated MDSCs in the colonic lamina propria (cLP)

Summary

Introduction

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. EZH2 regulates the differentiation of hematopoietic stem and progenitor cells, and further controls immune cell lineage development, including T, B, and natural killer cell lineages[17,18] Both innate and adaptive immune responses are modulated by EZH2 via promotion of macrophage M1 polarization[19], regulation of the differentiation and responses of Th1, Th2, and Th17 cells, and maintenance of Treg identity[20,21]. Our data identify EZH2 activity inhibition as a promising therapeutic approach to treat IBD These results warn against using EZH2 inhibitors for treating cancer clinically, as they may suppress beneficial anticancer immunity responses by increasing MDSC populations

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Results

Conclusion