EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis.
EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis.
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EZH2介导的Puma基因抑制调节非小细胞肺癌细胞增殖和顺铂诱导的细胞凋亡
DOI：
10.18632/oncotarget.10841
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发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Yang Y
中科院分区：
文献类型：
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作者：
Liu H;Li W;Yu X;Gao F;Duan Z;Ma X;Tan S;Yuan Y;Liu L;Wang J;Zhou X;Yang Y
多梳族蛋白（Polycomb group，PcG）是一类高度保守的表观遗传效应子，维持基因的沉默状态。EZH2是多梳阻遏复合物2（PRC2）的催化核心和最重要的组分之一。在非小细胞肺癌（NSCLC）细胞和原发性肺肿瘤中，我们发现PRC2组分（包括EZH2）过表达。高水平EZH2蛋白与NSCLC患者的总生存率相关。RNA干扰介导的EZH2表达的减弱减弱了这种情况下的恶性表型，对异种移植小鼠模型中的细胞增殖、锚定非依赖性生长和肿瘤发展产生抑制作用。出乎意料的是，我们发现，在EZH2的抑制中，p53上调的细胞凋亡调节因子（p53）表达被伴随诱导。这是通过EZH2直接结合Puma启动子，从而表观遗传抑制EZHA表达来实现的。此外，顺铂诱导的EZH2敲除NSCLC细胞的凋亡由于EZH2 A表达增加而升高。我们的工作揭示了一种新的表观遗传调控机制，控制EZH2的表达，并表明EZH2提供了一个候选的分子靶点NSCLC治疗和EZH2调节的EZH2诱导将协同增加铂类药物在非小细胞肺癌的敏感性。
Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non-small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2-regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers.