Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation
Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation
复制标题
靶向 EZH2 组蛋白甲基转移酶活性可减轻实验性肠道炎症
DOI：
10.1038/s41467-019-10176-2
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发表时间：
2019-06-03
影响因子：
16.6
通讯作者：
Zhu, Bo
中科院分区：
文献类型：
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作者：
Zhou, Jie;Huang, Shuo;Zhu, Bo
zeste同源物2增强子（EZH2）介导的组蛋白3赖氨酸27（H3K27Me3）的三甲基化对于免疫调节是关键的。然而，缺乏证据来说明EZH2酶的活性对炎症性肠病（IBD）期间肠道免疫应答的影响。在这里，我们报告说，抑制EZH2活性改善实验性肠道炎症和延迟结肠炎相关癌症的发病。此外，我们在结肠中鉴定了增加数量的功能性MDSC，这对于EZH2抑制剂活性是必需的。此外，EZH2活性的抑制促进了体外造血祖细胞生成MDSC，证明了EZH2在MDSC发育中以前未被认识到的作用。总之，这些发现表明EZH2抑制剂临床试验用于控制IBD的可行性。此外，这项研究确定了EZH2抑制剂的MDSC促进作用，这在其他治疗环境中可能是不可取的，应该在临床试验环境中解决。
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.