Mediator kinase inhibition further activates super-enhancer-associated genes in AML

Abstract

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 1, 2. BRD4 and CDK7 are positive regulators of SE-mediated transcription3,4,5. 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 6, 7, 8. 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.

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

“…Several groups are currently in the process of developing CDK8/19 inhibitors for cancer therapy applications (18). Although a recent paper reported significant toxicity of two CDK8/19-inhibiting small molecules (19), no toxicity has been reported in animal studies with other CDK8/19 inhibitors, including those used in the present work (3,8,16,17).…”

“…CDK8 has been identified as an oncogene implicated in colorectal (9), pancreatic (11), and breast (3,8,12,13) cancers and melanomas (14) and associated with the stem cell phenotype (15). CDK8/19 inhibition also has an antiproliferative effect in a subset of leukemias (16,17). Several groups are currently in the process of developing CDK8/19 inhibitors for cancer therapy applications (18).…”

CDK8 Kinase Activity Promotes Glycolysis

“…Many of these compounds have demonstrated efficacy in vitro and in preclinical models, most notably Cortistatin A in AML cells (Pelish et al, 2015), Senexin A in fibrosarcoma cells (Porter et al, 2012), and CCT251921 and MSC2530818 in CRC cells (Clarke et al, 2016). However, the most comprehensive evaluation of the therapeutic potential of dual CDK8/19 inhibitors to date, using two different classes of compounds, demonstrated only modest activity in a β-catenin-driven mouse model of CRC, and various adverse effects in rat and dog tolerability studies (Clarke et al, 2016).…”

The role of enhancers in cancer

“…It could thus potentially be destabilized by both increased and decreased transcriptional activity, which seems to be the case in at least some instances. For example, in several acute myeloid leukaemia cell lines, both inhibition and upregulation of the same super-enhancer-associated genes can inhibit growth 145 . HDAC inhibitors, in turn, seem to be active in different tumour types and to function through the regulation of different sets of genes 142,[146][147][148] , which indicates that they can perturb multiple types of pathological network.…”