BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal
BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal
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DOI：
10.1523/jneurosci.0968-09.2009
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发表时间：
2009-07-15
影响因子：
5.3
通讯作者：
Bernier, Gilbert
中科院分区：
文献类型：
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作者：
Abdouh, Mohamed;Facchino, Sabrina;Bernier, Gilbert
多形性胶质母细胞瘤(GBM)是最常见、最具侵袭性的脑肿瘤之一。在GBM中，CD133阳性的癌症启动细胞亚群表现出干细胞特征。多梳家族(PcG)和癌基因BMI1是多梳抑制复合体1(Prc1)的一部分，它通过改变染色质组织来调节基因的表达。在这里，我们发现BMI1在人类GBM肿瘤中表达，并在CD133阳性细胞中高度浓缩。使用表达短发夹状RNA的慢病毒稳定地敲除BMI1导致了体外克隆形成能力的抑制和体内脑瘤的形成。细胞生物学研究支持BMI1阻止CD133阳性细胞凋亡和/或分化为神经元和星形胶质细胞的观点，这取决于细胞环境。基因表达分析表明，BMI1抑制交替的肿瘤抑制途径，这些途径试图补偿Ink4a/ARF/P53缺失和PI(3)K/AKT过度活动。抑制PRC2的主要成分EZH2也会损害GBM肿瘤的生长。我们的结果表明，PcG蛋白参与了GBM肿瘤的生长，并需要维持癌症启动干细胞更新。
Glioblastoma multiforme (GBM) is one of the most common and aggressive types of brain tumors. In GBM, a subpopulation of CD133-positive cancer initiating cells displays stem cell characteristics. The Polycomb group (PcG) and oncogene BMI1 is part of the Polycomb repressive complex 1 (PRC1) that regulates gene expression by modifying chromatin organization. Here we show that BMI1 is expressed in human GBM tumors and highly enriched in CD133-positive cells. Stable BMI1 knockdown using short hairpin RNA-expressing lentiviruses resulted in inhibition of clonogenic potential in vitro and of brain tumor formation in vivo. Cell biology studies support the notion that BMI1 prevents CD133-positive cell apoptosis and/or differentiation into neurons and astrocytes, depending on the cellular context. Gene expression analyses suggest that BMI1 represses alternate tumor suppressor pathways that attempt to compensate for INK4A/ARF/P53 deletion and PI(3)K/AKT hyperactivity. Inhibition of EZH2, the main component of the PRC2, also impaired GBM tumor growth. Our results reveal that PcG proteins are involved in GBM tumor growth and required to sustain cancer initiating stem cell renewal.