Inhibition of BET bromodomain targets genetically diverse glioblastoma.
Inhibition of BET bromodomain targets genetically diverse glioblastoma.
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DOI：
10.1158/1078-0432.ccr-12-3066
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发表时间：
2013-04-01
期刊：
影响因子：
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通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
胶质母细胞瘤对传统治疗方法难以奏效。溴结构域和端外结构域(BET)蛋白是表观遗传阅读器，选择性地与组蛋白尾部的乙酰化赖氨酸残基结合。这些蛋白质最近成为NUT中线癌和几种血液癌的重要治疗靶点。在这项研究中，一种新型的BET溴域抑制剂JQ1在一组遗传异质性的胶质母细胞瘤样本中进行了治疗潜力的评估。JQ1的抗肿瘤作用由来自原代胶质母细胞瘤异种移植株的体外培养物和不同遗传背景的手术标本显示。在原位胶质母细胞瘤中评估了体内疗效。我们发现JQ1诱导了明显的G1期细胞周期停滞和细胞凋亡，这是通过下调BET家族的个别成员而表现出来的。JQ1治疗后，c-Myc、p21CIP1/WAF1、hTERT、Bcl2、Bclxl等在胶质母细胞瘤中起重要作用的基因表达发生明显变化。与在一些造血癌细胞系中观察到的不同，外源性c-Myc对胶质母细胞瘤细胞没有明显的保护作用。相反，异位表达的Bclxl部分挽救了JQ1诱导的细胞凋亡，p21CIP1/WAF1的敲除减弱了JQ1诱导的细胞周期停滞。为Akt过度激活或P53/Rb失活而进行基因工程的细胞不会影响JQ1的疗效，这表明这些频繁突变的信号通路可能不会对JQ1产生抗性。此外，JQ1显著抑制了原位胶质母细胞瘤的生长。我们的结果表明，BET溴域抑制剂有可能广泛用于治疗遗传多样性的胶质母细胞瘤肿瘤。
Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples. The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors. We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21CIP1/WAF1, hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors. Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors.