Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4+ T Cells.
Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4+ T Cells.
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DOI：
10.20900/immunometab20200013
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发表时间：
2020-01-01
期刊：
影响因子：
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通讯作者：
Sawalha, Amr H
中科院分区：
文献类型：
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作者：
Zheng, Xiaoqing;Tsou, Pei-Suen;Sawalha, Amr H
目的：系统性红斑狼疮（SLE）患者外周血CD 4 + T细胞中EZH 2的高表达。SLE患者疾病活动性增加与初始CD 4 + T细胞中的促炎表观遗传转变相关，可能由EZH 2介导。本研究旨在了解EZH 2在SLE CD 4 + T细胞中过度表达的上游机制。方法：从SLE患者中分离出幼稚CD 4 + T细胞，然后用抗CD 3/抗CD 28刺激。qPCR和Western印迹分别用于测量mRNA和蛋白质表达水平。2-脱氧-D-葡萄糖（2-DG）用于抑制糖酵解。使用雷帕霉素抑制mTORC 1信号传导。H2 O2诱导氧化应激。结果：由于SLE CD 4 + T细胞糖酵解增加，糖酵解调节EZH 2靶向的miR-26 a和miR-101，我们检测了抑制糖酵解对EZH 2表达的影响。2-DG显著抑制SLE CD 4 + T细胞EZH 2表达。此外，2-DG恢复了miR-26 a和miR-101的表达，表明2-DG对EZH 2的抑制发生在转录后水平。由于mTORC 1在SLE CD 4 + T细胞中被激活，部分原因是氧化应激增加，mTORC 1激活增加糖酵解，我们假设mTORC 1介导EZH 2表达增加。事实上，抑制mTORC 1增加了miR-26 a和miR-101，并抑制了SLE CD 4 + T细胞中的EZH 2表达。结论：SLE CD 4 + T细胞中EZH 2的表达增加是通过mTORC 1的激活和糖酵解增加介导的。抑制mTOR或糖酵解在SLE中的治疗作用可能部分通过抑制EZH 2介导。
OBJECTIVE: EZH2 is overexpressed in CD4+ T cells from patients with systemic lupus erythematosus (SLE). Increased disease activity in SLE patients is associated with a proinflammatory epigenetic shift in naive CD4+ T cells, likely mediated by EZH2. Here we aim to understand the upstream mechanisms underlying EZH2 overexpression in SLE CD4+ T cells.METHODS: Naive CD4+ T cells were isolated from SLE patients and then stimulated with anti-CD3/anti-CD28. qPCR and Western blotting were used to measure mRNA and protein expression levels, respectively. 2-Deoxy-d-glucose (2-DG) was used to inhibit glycolysis. mTORC1 signaling was inhibited using rapamycin. Oxidative stress was induced by H2O2.RESULTS: Because glycolysis is increased in SLE CD4+ T cells and glycolysis regulates miR-26a and miR-101, which target EZH2, we examined the effect of inhibiting glycolysis on EZH2 expression. 2-DG significantly inhibited EZH2 expression in SLE CD4+ T cells. In addition, 2-DG restored the expression of miR-26a and miR-101, suggesting that suppression of EZH2 by 2-DG occurs at the post-transcriptional level. Because mTORC1 is activated in SLE CD4+ T cells in part due to increased oxidative stress, and mTORC1 activation increases glycolysis, we hypothesized that mTORC1 mediates increased EZH2 expression. Indeed, inhibiting mTORC1 increased miR-26a and miR-101 and suppressed EZH2 expression in SLE CD4+ T cells. Further, H2O2 treatment increased EZH2 expression, however, this effect appears to be independent of miR-26a and miR-101.CONCLUSION: Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4+ T cells. Therapeutic effects from inhibiting mTOR or glycolysis in SLE might be in part mediated by suppression of EZH2.