Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells.
Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells.
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DOI：
10.1158/1535-7163.mct-09-0479
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发表时间：
2009-12
影响因子：
5.7
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Sun F;Chan E;Wu Z;Yang X;Marquez VE;Yu Q
多梳蛋白ezh2介导的基因沉默通过赖氨酸27 （H3K27）上的组蛋白H3甲基化参与乳腺肿瘤的发生。我们之前已经发现s -腺苷型同型半胱氨酸水解酶（SAHH）抑制剂3-Deazaneplanocin A （DZNep）可以调节组蛋白甲基化并破坏EZH2复合物。在这里，我们使用DZNep，连同其他染色质重塑剂，以及RNA干扰介导的EZH2缺失，探讨EZH2协同其他表观遗传成分在乳腺癌细胞基因调控中的作用。通过全基因组基因表达分析，结合广泛的组蛋白修饰的染色质免疫沉淀分析，我们已经确定了多种由EZH2单独或通过EZH2与HDAC和/或DNA甲基化协同作用调节的基因集。我们进一步发现肿瘤抗原GAGEs受不同的表观遗传机制以细胞环境依赖的方式调节，可能反映了乳腺癌的机制异质性。有趣的是，我们发现EZH2调节了一组显著的基因，这些基因在免疫应答和自分泌炎症网络中功能高度丰富，并且在EZH2扰动时它们的转录激活是癌症特异性的，这揭示了EZH2在调节癌症免疫中的潜在新作用。这些发现证明了人类癌症中表观遗传调控的复杂性和多样性，并强调了开发有效表观遗传基因再激活的组合药理学方法的重要性。
Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously showed that S-adenosylhomocysteine hydrolase (SAHH) inhibitor 3-Deazaneplanocin A (DZNep) can modulate histone methylation and disrupt EZH2 complex. Here, we used DZNep, together with other chromatin remodeling agents, as well as RNA interference-mediated EZH2 depletion, to probe the role of EZH2 in coordination with other epigenetic components in gene regulation in breast cancer cells. Through genome-wide gene expression analysis, coupled with extensive chromatin immunoprecipitation analysis of histone modifications, we have identified a variety of gene sets that are regulated either by EZH2 alone or through the coordinated action of EZH2 with HDAC and/or DNA methylation. We further found that tumor antigen GAGEs were regulated by distinct epigenetic mechanisms in a cell context-dependent manner, possibly reflecting mechanistic heterogeneity in breast cancer. Intriguingly, we found that EZH2 regulates a remarkable cohort of genes whose functions are highly enriched in immunoresponse and autocrine inflammation network, and their transcriptional activation upon EZH2 perturbation is cancer-specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings demonstrate the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation.