Remarkable Synergy When Combining EZH2 Inhibitors with YM155 Is H3K27me3-Independent.
Remarkable Synergy When Combining EZH2 Inhibitors with YM155 Is H3K27me3-Independent.
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实体瘤中基因表达的系统生物学分析鉴定了以EZH2为中心的27个特征，EZH2是多梳抑制复合物2的关键组分。我们的研究表明，BIRC5和EZH2抑制剂联合作用靶向27个基因网络可获得显著的抗癌协同效应，且与EZH2的组蛋白甲基转移酶活性无关。Global基因表达分析结合通路分析表明，BIRC5抑制剂YM155与EZH2抑制剂联合作用可诱导未折叠蛋白反应。 靶向同一生物网络中的多个分子可以使治疗功效最大化。在这项研究中，我们确定了一个在实体瘤中高度表达的27基因模块，编码包括EZH2和BIRC 5在内的可操作靶标。EZH2抑制剂和BIRC 5抑制剂YM155的组合产生显著的协同效应。EZH2抑制剂在该过程中的作用不依赖于polycomb抑制复合物2的组蛋白甲基转移酶活性。我们的研究揭示了通过同时靶向EZH2和BIRC 5来治疗实体瘤的潜在治疗方法。
Systems biology analysis of gene expression across solid tumors identifies a 27 signature that centers on EZH2, the key component of polycomb repressive complex 2. Our study demonstrates that targeting the 27 gene network by the combination of BIRC5 and EZH2 inhibitors achieves remarkable anticancer synergy that is independent of the histone methyltransferase activity of EZH2.Globlal gene expression analysis in combination with pathway analysis shows that combination of YM155, the BIRC5 inhibitor, with EZH2 inhibitors induces unfolded protein response. Targeting multiple molecules in the same biological network may maximize therapeutic efficacy. In this study, we identified a 27-gene module that is highly expressed in solid tumors, encoding actionable targets including EZH2 and BIRC5. The combination of EZH2 inhibitors and a BIRC5 inhibitor, YM155, results in a remarkable synergistic effect. The action of EZH2 inhibitors in this process is independent of the histone methyltransferase activity of polycomb repressive complex 2. Our study reveals a potential therapeutic approach for treating solid tumors by simultaneously targeting EZH2 and BIRC5.
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