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  • 1
    Publication Date: 2015-09-30
    Description: 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- CA66996/CA/NCI NIH HHS/ -- F31 CA180419/CA/NCI NIH HHS/ -- P01 CA066996/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- R01 CA170741/CA/NCI NIH HHS/ -- T32 GM08759/GM/NIGMS NIH HHS/ -- UL1 TR001082/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Oct 8;526(7572):273-6. doi: 10.1038/nature14904. Epub 2015 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, Colorado 80303, USA. ; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02215, USA. ; Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Martinsried, Germany. ; Max-Planck-Institut fur Biochemie, Am Kloperspitz 18, D-82152 Martinsried, Germany. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; Bioinfo, Plantagenet, Ontario K0B 1L0, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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