EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression.
EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression.
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DOI：
10.1158/1541-7786.mcr-10-0511
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发表时间：
2011-04
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影响因子：
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通讯作者：
Hornyak TJ
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文献类型：
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作者：
Fan T;Jiang S;Chung N;Alikhan A;Ni C;Lee CC;Hornyak TJ
多梳组蛋白（Polycomb group proteins，PcG），如Zeste同源物增强子2（Enhancer of zeste homolog 2，EZH 2），是通过识别和修饰组蛋白甲基化和染色质结构发挥作用的表观遗传转录抑制因子。PcG的靶点包括控制细胞周期进程和细胞衰老的细胞周期调节蛋白。衰老是黑素细胞痣的特征，良性黑素细胞增殖可以是恶性黑色素瘤的前体。在这项研究中，我们发现EZH 2在黑色素细胞痣中不存在，但在许多或大多数转移性黑色素瘤细胞中表达，在功能上抑制人黑色素瘤细胞的衰老状态。黑素瘤细胞中的EZH 2消耗抑制细胞增殖，恢复细胞衰老表型的特征，并抑制体内黑素瘤异种移植物的生长。p21/CDKN 1A在EZH 2敲低后以p53非依赖性方式被激活，并显著促进细胞周期停滞和诱导衰老表型。EZH 2耗竭从CDKN 1A转录起始位点和下游区域去除组蛋白脱乙酰酶1（HDAC 1），从而增强组蛋白3整体和在CDKN 1A处的乙酰化。这导致RNA聚合酶II的募集，导致p21/CDKN 1A活化。EZH 2的消耗协同激活p21/CDKN 1A表达与HDAC抑制剂阿司他汀A的组合。由于黑色素瘤通常保留激活p21的野生型p53功能，我们的研究结果描述了一种新的机制，即肿瘤进展过程中EZH 2激活抑制p21，从而抑制细胞衰老和增强致瘤性。
Polycomb group proteins (PcG) such as Enhancer of zeste homolog 2 (EZH2) are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. Targets of PcG include cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. Senescence is a characteristic of melanocytic nevi, benign melanocytic proliferations that can be precursors of malignant melanoma. In this study, we report that EZH2, which we find absent in melanocytic nevi but expressed in many or most metastatic melanoma cells, functionally suppresses the senescent state in human melanoma cells. EZH2 depletion in melanoma cells inhibits cell proliferation, restores features of a cellular senescence phenotype, and inhibits growth of melanoma xenografts in vivo. p21/CDKN1A is activated upon EZH2 knockdown in a p53-independent manner and contributes substantially to cell cycle arrest and induction of a senescence phenotype. EZH2 depletion removes histone deacetylase 1 (HDAC1) from the CDKN1A transcriptional start site and downstream region, enhancing histone 3 acetylation globally and at CDKN1A. This results in recruitment of RNA polymerase II, leading to p21/CDKN1A activation. Depletion of EZH2 synergistically activates p21/CDKN1A expression in combination with the HDAC inhibitor trichostatin A. Since melanomas often retain wild-type p53 function activating p21, our findings describe a novel mechanism whereby EZH2 activation during tumor progression represses p21, leading to suppression of cellular senescence and enhanced tumorigenicity.