G9a inhibition induced PKM2 regulates autophagic responses
G9a inhibition induced PKM2 regulates autophagic responses
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DOI：
10.1016/j.biocel.2016.07.009
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发表时间：
2016-09-01
影响因子：
4
通讯作者：
Sen, Ellora
中科院分区：
文献类型：
--
作者：
Ahmad, Fahim;Dixit, Deobrat;Sen, Ellora
已知组蛋白甲基转移酶G9 a的表观遗传调节控制自噬反应。由于自噬和代谢稳态之间的联系被广泛接受，我们研究了G9 a是否影响神经胶质瘤细胞中的代谢回路以影响自噬反应。药理学抑制和siRNA介导的G9 a敲低均增加胶质瘤细胞中的自噬标记物LC 3B。G9 a抑制剂BIX-01294（BIX）诱导HIF-1 α表达和活性的Akt依赖性增加。抑制Akt-HIF-1 α轴逆转BIX介导的（i）LC 3B表达增加和（ii）YAP 1磷酸化减少。YAP 1过表达消除了BIX诱导的LC 3B表达增加。有趣的是，BIX诱导的代谢模型TIGAR（TP 53诱导的糖酵解和凋亡调节因子）和PKM 2（丙酮酸激酶M2）的增加对于BIX介导的变化至关重要，因为用TIGAR突变体或PKM 2 siRNA转染逆转了BIX介导的pYAP 1和LOB表达的改变。与体外观察一致，BIX对异种移植胶质瘤小鼠模型的肿瘤负荷没有显著影响。BIX处理的异种移植组织中LC 3B和PKM 2升高伴随着YAP 1水平降低。综上所述，我们的研究结果表明，Akt-HIF-1 α轴驱动的PKM 2-YAP 1串扰激活神经胶质瘤细胞在G9 a抑制后的自噬反应。(C)2016爱思唯尔有限公司版权所有
Epigenetic regulation by histone methyltransferase G9a is known to control autophagic responses. As the link between autophagy and metabolic homeostasis is widely accepted, we investigated whether G9a affects metabolic circuitries to affect autophagic response in glioma cells. Both pharmacological inhibition and siRNA mediated knockdown of G9a increased autophagy marker LC3B in glioma cells. G9a inhibitor BIX-01294(BIX) induced Akt-dependent increase in HIF-1 alpha expression and activity. Inhibition of Akt-HIF-1 alpha axis reversed BIX-mediated (i) increase in LC3B expression and (ii) decrease in Yes-associated protein 1 (YAP1) phosphorylation. YAP1 over-expression abrogated BIX induced increase in LC3B expression. Interestingly, BIX induced increase in metabolic modelers TIGAR (TP53-induced glycolysis and apoptosis regulator) and PKM2 (Pyruvate kinase M2) were crucial for BIX-mediated changes, as transfection with TIGAR mutant or PKM2 siRNA reversed BIX-mediated alterations in pYAP1 and LOB expression. Coherent with the in vitro observation, BIX had no significant effect on the tumor burden in heterotypic xenograft glioma mouse model. Elevated LC3B and PKM2 in BIX-treated xenograft tissue was accompanied by decreased YAP1 levels. Taken together, our findings suggest that Akt-HIF-1 alpha axis driven PKM2-YAP1 cross talk activates autophagic responses in glioma cells upon G9a inhibition. (C) 2016 Elsevier Ltd. All rights reserved.