Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.

中文翻译：

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通过联合抑制 BMI1 和 EZH2 靶向神经胶质瘤干细胞。


胶质母细胞瘤是由血管生成和假栅栏坏死定义的致命癌症。在这里，我们证明这些组织学特征与不同的转录程序相关，血​​管区域显示原神经特征，缺氧区域显示间充质模式。由于这些区域含有神经胶质瘤干细胞（GSC），我们研究了这两个生态位的表观遗传调控。前神经、血管周围 GSC 激活 EZH2，而缺氧区域的间充质 GSC 表达 BMI1 蛋白，由于 E3 连接酶 RNF144A 的下调，BMI1 蛋白促进细胞在应激下的存活。通过遗传和药物抑制，我们发现原神经 GSC 对 EZH2 破坏优先敏感，而间充质 GSC 对 BMI1 抑制更敏感。鉴于胶质母细胞瘤同时含有原神经和间充质 GSC，EZH2 和 BMI1 联合靶向在培养和体内均被证明比单独使用任一药物更有效，这表明同时靶向胶质母细胞瘤内多个表观遗传调节因子的策略可能有效克服瘤内肿瘤引起的治疗耐药性。异质性。