Epigenetic silencing and activation of transcription: influence on the radiation sensitivity of glioma cell lines
Epigenetic silencing and activation of transcription: influence on the radiation sensitivity of glioma cell lines
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DOI：
10.1080/09553002.2017.1270472
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发表时间：
2017-05-01
影响因子：
2.6
通讯作者：
Stuschke, Martin
中科院分区：
文献类型：
--
作者：
Sak, Ali;Kuebler, Dennis;Stuschke, Martin
目的：揭示EZH2及其对手ASHL2（一种多梳蛋白和三胸组蛋白）对胶质瘤细胞系放射反应性的作用。材料与方法：siRNA抑制胶质瘤细胞系中EZH2和ASHL2的表达。评估了对组蛋白甲基化、基因表达、DNA 损伤修复信号、细胞周期检查点、细胞凋亡和肿瘤控制的影响。结果：EZH2 (EZH2i) 的抑制导致转录失调，其中 544 个基因上调，445 个基因下调。相比之下，ASH2L 抑制 (ASH2Li) 具有相反的作用，上调 289 个基因，下调 970 个基因。 EZH2i 和 ASH2Li 分别显着降低 H3K27 的甲基化并增加 H3K9 的甲基化。 EZH2i 和 ASH2Li 分别在 IR 后 24 小时显着增加和减少残留 H2AX 病灶的数量。前者显着增加了辐射诱导的 G2/M 期细胞周期停滞和细胞凋亡，而 ASH2Li 则降低了这两者。此外，放射反应曲线显着偏移-1.22+0.23Gy (p
Purpose: To uncover the role of EZH2 and its opponent ASHL2, a polycomb and trithorax group protein, respectively, on the radioresponsiveness of glioma cell lines.Materials and methods: Expression of EZH2 and ASHL2 was inhibited by siRNA in glioma cell lines. The effect on histone methylation, gene expression, DNA damage repair signaling, cell cycle checkpoints, apoptosis and tumor control were evaluated.Results: Inhibition of EZH2 (EZH2i) led to a transcriptional dysregulation with upregulation of 544 and downregulation of 445 genes. In comparison, ASH2L inhibition (ASH2Li) had an opposed effect with upregulation of 289 and downregulation of 970 genes. EZH2i and ASH2Li significantly reduced methylation of H3K27 and increased methylation of H3K9, respectively. EZH2i and ASH2Li significantly increased and decreased the number of residual H2AX foci at 24h after IR, respectively. The former significantly increased radiation-induced cell cycle arrest in G2/M and apoptotic cell death, while ASH2Li decreased both. In addition, a significant shift of the radioresponse curve by -1.22+0.23Gy (p