EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection.
EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection.
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EZH2 抑制主动脉血管平滑肌细胞的自噬细胞死亡，从而影响主动脉夹层。
DOI：
10.1038/s41419-017-0213-2
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Jiang DS
中科院分区：
文献类型：
--
作者：
Li R;Yi X;Wei X;Huo B;Guo X;Cheng C;Fang ZM;Wang J;Feng X;Zheng P;Su YS;Masau JF;Zhu XH;Jiang DS
zeste同源物2增强子（EZH 2）是一种甲基转移酶，其使组蛋白H3的赖氨酸-27二甲基化和三甲基化，主要作为转录抑制因子发挥作用，并且在各种癌症中起关键作用。在这里，我们报告了EZH 2在调节影响主动脉夹层（AD）的血管平滑肌细胞（VSMCs）的自噬细胞死亡（ACD）中的新功能。UNC 1999抑制EZH 2活性或敲低EZH 2导致VSMC损失，而EZH 2过表达促进VSMC生长，并且EZH 2对VSMC的这些作用不依赖于增殖和凋亡。有趣的是，在EZH 2抑制或缺乏的VSMC中鉴定出更多的自噬空泡和增加的LC 3 II蛋白水平。此外，当与对应物相比时，单独的氯喹或氯喹与雷帕霉素处理导致EZH 2抑制或敲低的VSMCs中更多的LC 3 II积累，这表明EZH 2负调控自噬体形成。与此相结合，ATG 5和ATG 7蛋白水平在EZH 2抑制或缺陷的VSMC中显著增加，并且ATG 5或ATG 7敲低实际上挽救了由EZH 2抑制或敲低诱导的VSMC损失。此外，我们还发现EZH 2对VSMCs ACD的影响是通过MEK-ERK 1/2信号通路而不是AMPKα、mTOR或AKT通路来实现的。此外，EZH 2抑制或敲低对VSMC的不利影响在很大程度上被MEK 1抑制剂PD 98059逆转。更重要的是，AD患者主动脉壁中EZH 2表达水平降低表明其对VSMC损失和AD发生的贡献。这些结果表明EZH 2通过调节ATG 5和ATG 7的表达以及MEK-ERK 1/2信号通路影响VSMCs的ACD和AD的病理过程。我们迄今尚未认识到的发现表明，EZH 2激活具有治疗或预防AD的潜力。
Enhancer of zeste homolog 2 (EZH2), a methyltransferase that di- and tri-methylates lysine-27 of histone H3, largely functions as a transcriptional repressor, and plays a critical role in various kinds of cancers. Here we report a novel function of EZH2 in regulating autophagic cell death (ACD) of vascular smooth muscle cells (VSMCs) that affect aortic dissection (AD). Inhibition of EZH2 activity by UNC1999 or knockdown EZH2 resulted in VSMC loss, while overexpression of EZH2 facilitated VSMC growth, and these effects of EZH2 on VSMCs were independent of proliferation and apoptosis. Interestingly, more autophagic vacuoles and increased LC3II protein levels were identified in VSMCs with EZH2 inhibition or deficiency. Moreover, when compared with counterparts, chloroquine alone, or chloroquine with rapamycin treatment led to more LC3II accumulation in EZH2 inhibited or knockdown VSMCs, which indicated that EZH2 negatively regulated autophagosome formation. In conjunction to this, ATG5 and ATG7 protein levels were remarkably increased in EZH2 inhibited or deficient VSMCs, and ATG5 or ATG7 knockdown virtually rescued VSMC loss induced by EZH2 inhibition or knockdown. In addition, we found that the MEK–ERK1/2 signaling pathway, but not AMPKα, mTOR, or AKT pathway, is responsible for the impact of EZH2 on ACD of VSMCs. Additionally, the adverse effects of EZH2 inhibition or knockdown on VSMCs were largely reversed by PD98059, an inhibitor of MEK1. More importantly, decreased EZH2 expression levels in the aortic wall of patients with AD indicated its contribution to VSMC loss and AD occurrence. Overall, these findings revealed that EZH2 affects ACD of VSMCs and the pathologic process of AD via regulating ATG5 and ATG7 expression and MEK–ERK1/2 signaling. Our hitherto unrecognized findings indicate that EZH2 activation has therapeutic or preventive potential for AD.
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DOI：
10.1158/1078-0432.ccr-16-2020
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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