Cancer Biology and Pharmacology, Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore 138672.
Mol Cancer Ther. 2009 Dec;8(12):3191-202. doi: 10.1158/1535-7163.MCT-09-0479.
Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously shown that S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A can modulate histone methylation and disrupt EZH2 complex. Here, we used 3-deazaneplanocin A, 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 that their transcriptional activation upon EZH2 perturbation is cancer specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings show the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation.
多梳蛋白 EZH2 介导的基因沉默通过组蛋白 H3 赖氨酸 27（H3K27）的甲基化参与乳腺癌发生。我们之前已经表明，S-腺苷同型半胱氨酸水解酶抑制剂 3-去氮杂胞苷 A 可以调节组蛋白甲基化并破坏 EZH2 复合物。在这里，我们使用 3-去氮杂胞苷 A 与其他染色质重塑剂以及 RNA 干扰介导的 EZH2 耗竭一起，探究 EZH2 与其他表观遗传成分在乳腺癌细胞基因调控中的协调作用。通过全基因组基因表达分析，以及对组蛋白修饰的广泛染色质免疫沉淀分析，我们已经确定了各种受 EZH2 单独调节或通过 EZH2 与 HDAC 和/或 DNA 甲基化的协调作用调节的基因集。我们进一步发现，肿瘤抗原 GAGEs 以细胞上下文依赖的方式受不同的表观遗传机制调节，这可能反映了乳腺癌中的机制异质性。有趣的是，我们发现 EZH2 调节了一组显著的基因，这些基因的功能高度富集在免疫反应和自分泌炎症网络中，并且它们在 EZH2 扰动时的转录激活是癌症特异性的，揭示了 EZH2 在调节癌症免疫方面的潜在新作用。这些发现表明了人类癌症中表观遗传调控的复杂性和多样性，并强调了开发组合药物治疗方法以有效进行表观遗传基因再激活的重要性。
