Glioblastoma multiforme (GBM) is an incurable primary brain tumor containing a sub-population of cancer stem cells (CSCs). Polycomb Repressive Complex (PRC) proteins BMI1 and EZH2 are enriched in CSCs, promoting clonogenic growth and resistance to genotoxic therapies. We report here that when used at appropriate concentrations, pharmaceutical inhibitors of BMI1 could efficiently prevent GBM colony growth and CSC self-renewal in vitro and significantly extend lifespan in terminally ill tumor-bearing mice. Notably, molecular analyses revealed that the commonly used PTC596 molecule targeted both BMI1 and EZH2, possibly providing beneficial therapeutic effects in some contexts. On the other hand, treatment with PTC596 resulted in instant reactivation of EZH2 target genes and induction of a molecular program of epithelial-mesenchymal transition (EMT), possibly explaining the modified phenotype of some PTC596-treated tumors. Treatment with a related but more specific BMI1 inhibitor resulted in tumor regression and maintenance of cell identity. We conclude that inhibition of BMI1 alone is efficient at inducing GBM regression, and that dual inhibition of BMI1 and EZH2 using PTC596 may be also beneficial but only in specific contexts.

中文翻译：

---

BMI1抑制剂PTC596的脱靶作用可驱动多形性胶质母细胞瘤中的上皮-间质转化。

多形胶质母细胞瘤（GBM）是一种不可治愈的原发性脑肿瘤，其中包含癌症干细胞（CSC）的亚群。聚梳抑制复合物（PRC）蛋白BMI1和EZH2富含CSC，可促进克隆形成生长和对基因毒性疗法的抵抗力。我们在这里报告，当以适当的浓度使用时，BMI1的药物抑制剂可以有效地阻止GBM菌落的生长和体外CSC的自我更新，并显着延长绝症的荷瘤小鼠的寿命。值得注意的是，分子分析表明，常用的PTC596分子同时靶向BMI1和EZH2，在某些情况下可能提供有益的治疗效果。另一方面，使用PTC596进行治疗可立即重新激活EZH2目标基因并诱导上皮-间质转化（EMT）分子程序，可能解释了一些经PTC596治疗的肿瘤的修饰表型。用相关但更特异性的BMI1抑制剂治疗导致肿瘤消退并维持细胞身份。我们得出的结论是，单独抑制BMI1可以有效诱导GBM退化，并且使用PTC596对BMI1和EZH2的双重抑制也可能有益，但仅在特定情况下有效。