Pelish Henry E, Liau Brian B, Nitulescu Ioana I, Tangpeerachaikul Anupong, Poss Zachary C, Da Silva Diogo H, Caruso Brittany T, Arefolov Alexander, Fadeyi Olugbeminiyi, Christie Amanda L, Du Karrie, Banka Deepti, Schneider Elisabeth V, Jestel Anja, Zou Ge, Si Chong, Ebmeier Christopher C, Bronson Roderick T, Krivtsov Andrei V, Myers Andrew G, Kohl Nancy E, Kung Andrew L, Armstrong Scott A, Lemieux Madeleine E, Taatjes Dylan J, Shair Matthew D
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, CO 80303, USA.
Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904. Epub 2015 Sep 28.
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the 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 report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces 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 transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the 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.
超级增强子（SEs）由大量紧密结合中介体复合物、转录因子和染色质调节因子的增强子簇组成，驱动与细胞特性和疾病相关的基因的高表达，如谱系控制转录因子和癌基因。BRD4和CDK7是SE介导转录的正调节因子。相比之下，SE相关基因的负调节因子尚未得到充分描述。在这里，我们表明，与中介体相关的激酶细胞周期蛋白依赖性激酶8（CDK8）和CDK19抑制急性髓系白血病（AML）细胞中关键SE相关基因的激活增加。我们报告说，天然产物皮质抑素A（CA）选择性抑制中介体激酶，在体外和体内具有抗白血病活性，并且在CA敏感的AML细胞系中不成比例地诱导SE相关基因的上调，而在CA不敏感的细胞系中则不然。在AML细胞中，CA上调了具有肿瘤抑制和谱系控制功能的SE相关基因，包括转录因子CEBPA、IRF8、IRF1和ETV6（参考文献6 - 8）。BRD4抑制剂I-BET151下调了这些SE相关基因，但也具有抗白血病活性。单独增加或减少这些转录因子的表达会抑制AML细胞生长，这表明白血病细胞对SE相关基因的剂量敏感。我们的结果表明，中介体激酶可以在特定细胞类型中负调节SE相关基因的表达，并且可以作为AML的一种治疗方法进行药物靶向治疗。
