Targeting of BMI-1 with PTC-209 inhibits glioblastoma development
Targeting of BMI-1 with PTC-209 inhibits glioblastoma development
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PTC-209 靶向 BMI-1 可抑制胶质母细胞瘤的发展
DOI：
10.1080/15384101.2018.1469872
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发表时间：
2018-01-01
期刊：
影响因子：
4.3
通讯作者：
Wu, Xudong
中科院分区：
文献类型：
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作者：
Kong, Yu;Ai, Chunbo;Wu, Xudong
摘要多形性胶质母细胞瘤(GBM)是最常见、最具侵袭性的脑肿瘤，对现有的治疗方法难以奏效。癌基因BMI-1是多梳抑制复合体1(Prc1)的成员，在多种人类癌症中发挥重要作用，成为一个有吸引力的治疗靶点。在这里，我们发现Bmi-1在GBM中高表达，尤其是在胶质母细胞瘤干细胞(GSCs)中表达。然后，我们全面研究了新型BMI-1特异性抑制剂PTC-209的抗GBM作用。我们发现，PTC-209在微米浓度下有效地下调Bmi-1的表达和组蛋白H2 AK119ub1的水平。在体外，PTC-209有效地抑制胶质母细胞瘤细胞的增殖和迁移，并抑制GSC的自我更新。对胶质母细胞瘤和PTC-209处理的GBM细胞的TCGA数据集的转录分析表明，PTC-209逆转了与BMI-1过表达相关的转录程序的改变。染色质免疫沉淀分析证实，去下调的抑癌基因属于Bmi-1靶基因，PTC-209处理后其启动子上的H_2AK119ub1的浓缩水平降低。值得注意的是，在小鼠原位异种移植模型中，PTC-209显著抑制了胶质母细胞瘤的生长。因此，我们的研究为靶向BMI-1的抑制剂作为抗GBM治疗的潜在应用提供了概念验证。
ABSTRACT Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and refractory to existing therapies. The oncogene BMI-1, a member of Polycomb Repressive Complex 1 (PRC1) plays essential roles in various human cancers and becomes an attractive therapeutic target. Here we showed that BMI-1 is highly expressed in GBM and especially enriched in glioblastoma stem cells (GSCs). Then we comprehensively investigated the anti-GBM effects of PTC-209, a novel specific inhibitor of BMI-1. We found that PTC-209 efficiently downregulates BMI-1 expression and the histone H2AK119ub1 levels at microM concentrations. In vitro, PTC-209 effectively inhibits glioblastoma cell proliferation and migration, and GSC self-renewal. Transcriptomic analyses of TCGA datasets of glioblastoma and PTC-209-treated GBM cells demonstrate that PTC-209 reverses the altered transcriptional program associated with BMI-1 overexpression. And Chromatin Immunoprecipitation assay confirms that the derepressed tumor suppressor genes belong to BMI-1 targets and the enrichment levels of H2AK119ub1 at their promoters is decreased upon PTC-209 treatment. Strikingly, the glioblastoma growth is significantly attenuated by PTC-209 in a murine orthotopic xenograft model. Therefore our study provides proof-of-concept for inhibitors targeting BMI-1 in potential applications as an anti-GBM therapy.