Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation

Jie Zhou, Shuo Huang, Zhongyu Wang, Jiani Huang, Liang Xu, Xuefeng Tang, Yisong Y. Wan, Qi-jing Li, Alistair L. J. Symonds, Haixia Long () and Bo Zhu ()
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Jie Zhou: Third Military Medical University
Shuo Huang: Third Military Medical University
Zhongyu Wang: Third Military Medical University
Jiani Huang: Third Military Medical University
Liang Xu: Third Military Medical University
Xuefeng Tang: Third Military Medical University
Yisong Y. Wan: University of North Carolina at Chapel Hill
Qi-jing Li: Duke University Medical Center
Alistair L. J. Symonds: University of London
Haixia Long: Third Military Medical University
Bo Zhu: Third Military Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10176-2

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