Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
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DOI：
10.1038/nature14904
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发表时间：
2015-10-08
期刊：
影响因子：
64.8
通讯作者：
Shair MD
中科院分区：
文献类型：
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作者：
Pelish HE;Liau BB;Nitulescu II;Tangpeerachaikul A;Poss ZC;Da Silva DH;Caruso BT;Arefolov A;Fadeyi O;Christie AL;Du K;Banka D;Schneider EV;Jestel A;Zou G;Si C;Ebmeier CC;Bronson RT;Krivtsov AV;Myers AG;Kohl NE;Kung AL;Armstrong SA;Lemieux ME;Taatjes DJ;Shair MD
超级增强子（SE）由密集装载有介体复合物、转录因子（TF）和染色质调节剂的大簇增强子组成，驱动与细胞身份和疾病有关的基因的高表达，例如谱系控制TF和癌基因。BRD 4和CDK 7是SE介导的转录的正调控因子。相反，SE相关基因的负调控因子尚未得到很好的描述。在这里，我们报告，介体相关激酶细胞周期蛋白依赖性激酶8（CDK 8）和CDK 19抑制增加激活的关键SE相关基因在急性髓性白血病（AML）细胞。我们确定，天然产物皮质抑素A（CA）选择性地抑制介质激酶，在体外和体内具有抗白血病活性，并不成比例地诱导CA敏感的AML细胞系中SE相关基因的上调，但在CA不敏感的细胞系中则不然。在AML细胞中，CA上调SE相关基因，具有肿瘤抑制和谱系控制功能，包括TF CEBPA，IRF 8，IRF 1和ETV 6。BRD 4抑制剂I-BET 151下调这些SE相关基因，但也具有抗白血病活性。单独增加或减少这些TF的表达抑制AML细胞生长，提供了白血病细胞对SE相关基因剂量敏感的证据。我们的研究结果表明，介体激酶可以负调控SE相关的基因表达在特定的细胞类型，并可以作为一种治疗方法，AML的靶向治疗。
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors (TFs), and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling TFs and oncogenes . BRD4 and CDK7 are positive regulators of SE-mediated transcription. In contrast, negative regulators of SE-associated genes have not been well described. Here we report that Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We determined that the natural product cortistatin A (CA) selectively inhibited Mediator kinases, had antileukaemic activity in vitro and in vivo, and disproportionately induced upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the TFs CEBPA, IRF8, IRF1 and ETV6 . The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has antileukaemic activity. Individually increasing or decreasing expression of these TFs suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types and can be pharmacologically targeted as a therapeutic approach to AML.