Inhibition enhancer of zeste homologue 2 promotes senescence and apoptosis induced by doxorubicin in p53 mutant gastric cancer cells
Inhibition enhancer of zeste homologue 2 promotes senescence and apoptosis induced by doxorubicin in p53 mutant gastric cancer cells
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DOI：
10.1111/cpr.12103
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发表时间：
2014-06-01
影响因子：
8.5
通讯作者：
Tao, K.
中科院分区：
文献类型：
--
作者：
Bai, J.;Ma, M.;Tao, K.
目的Zeste同源物增强子2（EZH 2）作为组蛋白甲基转移酶参与表观遗传沉默。虽然EZH 2在许多癌症中过表达，并参与恶性细胞增殖和侵袭，但EZH 2在DNA损伤诱导的衰老中的作用迄今为止仍不清楚。在这项研究中，我们试图探索EZH 2耗尽沿着暴露的阿霉素（DOX）的结果，以及相关的机制，在胃癌cells.Materials and MethodsHere，衰老诱导的DNA损伤在胃癌细胞中实现了DOX治疗。EZH 2通过用siRNA转染或用（-）-表没食子儿茶素-3-没食子酸酯（一种靶向抑制剂）处理而下调。衰老相关的半乳糖苷酶（SA-半乳糖）和衰老相关的异染色质灶的形成被用来识别细胞衰老。采用流式细胞术和MTT法检测EZH 2缺失对细胞周期、凋亡和增殖的影响。Western blotting检测p53-p21轴活性的变化。从机制上讲，EZH 2耗竭不仅在细胞衰老过程中与DNA损伤协同作用，而且还促进了p53突变细胞的凋亡。然而，它没有合作关系DOX在p53野生型cells.ConclusionsThese data help unraveled a critical role for EZH 2 in senescence and apoptosis in gastric cancer cells and that p53 genomic status was associated with different cell responses to EZH 2 silencing.
ObjectivesEnhancer of zeste homologue 2 (EZH2) is crucially involved in epigenetic silencing by acting as a histone methyltransferase. Although EZH2 is overexpressed in many cancers and is involved in malignant cell proliferation and invasion, the role of EZH2 in senescence induced by DNA damage has up to now remained largely unknown. In this study, we sought to explore the outcome of EZH2 depletion along with exposure of doxorubicin (DOX), and related mechanisms, in gastric cancer cells.Materials and methodsHere, senescence induced by DNA damage was achieved in gastric cancer cells by DOX treatment. EZH2 was downregulated by transfection with siRNA or treated with (-)-epigallocatechin-3-gallate, a targeted inhibitor. Senescence-associated galactosidase (SA--gal) and formation of senescence-associated heterochromatin foci were used to identify cell senescence. To investigate effects of EZH2 depletion on the cell cycle, apoptosis and proliferation, flow cytometry and MTT analysis were employed. Changes in p53-p21 axis activation were detected by Western blotting.ResultsWe found that cell proliferative arrest caused by DOX could be promoted by EZH2 depletion. Mechanistically, EZH2 depletion not only worked in coordination with DNA damage during the progression of cell senescence but also promoted apoptosis in p53 mutant cells. However, it had no cooperative relationship with DOX in p53 wild-type cells.ConclusionsThese data help unravel a crucial role for EZH2 in senescence and apoptosis in gastric cancer cells and that p53 genomic status was associated with different cell responses to EZH2 silencing.