CDK7 inhibition is a novel therapeutic strategy against GBM both in vitro and in vivo
CDK7 inhibition is a novel therapeutic strategy against GBM both in vitro and in vivo
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CDK7 抑制是一种针对 GBM 的体外和体内新型治疗策略
DOI：
10.2147/cmar.s183696
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发表时间：
2018-01-01
影响因子：
3.3
通讯作者：
Ma, Jie
中科院分区：
文献类型：
--
作者：
Meng, Wei;Wang, Jiajia;Ma, Jie
多形性胶质母细胞瘤（GBM）是目前成人最常见的恶性肿瘤之一。目前的GBM疗法极大地受到GBM细胞的高度异质性和适应性的影响，这表明迫切需要替代治疗选择。在这项研究中，我们专注于确定针对GBM的新的表观遗传靶向策略。方法筛选表观遗传调节小分子，并在体外和体内验证其抑制GBM的作用。还使用遗传靶向方法来验证所识别试剂的靶向抑制作用。此外，通过对药物处理的GBM细胞和GBM肿瘤数据库的综合分析来研究所鉴定的药剂的抑制机制。结果CDK 7共价抑制剂THZ 1是我们筛选的最佳靶点之一，其在体外和体内均证实具有抗GBM活性。通过CRISPR-Cas9或RNA干扰抑制CDK 7也显著破坏GBM细胞生长。此外，对多个GBM肿瘤数据库的分析一致地显示，与正常脑组织和低级别胶质瘤相比，GBM中CDK 7表达显著升高。CDK 7高表达与胶质瘤和GBM的预后不良相关。从机制上讲，THZ 1治疗导致GBM细胞中的整体基因转录受到相当大的破坏，优先靶向与超级增强子（SE）相关的基因。我们还发现THZ 1敏感基因和SE相关基因对GBM生长具有重要作用。结论我们的研究表明，通过抑制CDK 7靶向SE相关的转录成瘾可能是一种有效的治疗GBM的策略。
Background Glioblastoma multiforme (GBM) remains to be one of the top lethal cancer types for adult to date. Current GBM therapies suffer greatly from the highly heterogeneous and adaptable nature of GBM cells, indicating an urgent need of alternative therapeutic options. In this study, we focused on identifying novel epigenetic targeted strategy against GBM. Methods A collection of epigenetic modulating small molecules were subjected to anti-GBM screening and the inhibitory effect of identified agent was validated both in vitro and in vivo. Genetic targeting approaches were also used to verify the on-target inhibitory effect of identified agent. Furthermore, the inhibitory mechanism of identified agent was investigated by integrative analyses of drug-treated GBM cells and GBM tumor databases. Results The covalent CDK7 inhibitor THZ1 was one of the top hits in our screening and its anti-GBM activity was confirmed both in vitro and in vivo. CDK7 inhibition through CRISPR-Cas9 or RNA interference also markedly disrupted GBM cell growth. Furthermore, analyses of multiple GBM tumor databases consistently revealed that CDK7 expression was significantly elevated in GBM compared with normal brain tissues and lower grade gliomas. Higher CDK7 expression was correlated with worse prognosis for both glioma and GBM. Mechanistically, THZ1 treatment led to considerable disruption of global gene transcription in GBM cells, preferentially targeting those associated with super-enhancers (SEs). We also showed that THZ1 sensitive and SE-related genes had important roles for GBM growth. Conclusion Our study shows that targeting SE-associated transcription addiction by CDK7 inhibition could be an effective therapeutic strategy against GBM.