Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells

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http://hdl.handle.net/10138/298268

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Kuuluvainen , E , Domenech-Moreno , E , Niemela , E H & Makela , T P 2018 , ' Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells ' , Molecular and Cellular Biology , vol. 38 , no. 12 , UNSP e00573-17 . https://doi.org/10.1128/MCB.00573-17

Title: Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells
Author: Kuuluvainen, Emilia; Domenech-Moreno, Eva; Niemela, Elina H.; Makela, Tomi P.
Contributor: University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Helsinki Institute of Life Science HiLIFE, Joint Activities
University of Helsinki, Research Programs Unit
University of Helsinki, Helsinki Institute of Life Science HiLIFE, Joint Activities
Date: 2018-06
Language: eng
Number of pages: 15
Belongs to series: Molecular and Cellular Biology
ISSN: 0270-7306
URI: http://hdl.handle.net/10138/298268
Abstract: In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by beta-catenin, which has previously been shown to associate with MED12. Importantly, beta-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4.
Subject: BRD4
CDK19
CDK8
cancer
MED12
MED13
MED13L
Mediator
superenhancer
transcription
SUPER-ENHANCERS
TRANSCRIPTION FACTORS
SELECTIVE-INHIBITION
COLORECTAL-CANCER
EXPRESSION
RNA
MICE
ELONGATION
LEUKEMIA
1182 Biochemistry, cell and molecular biology
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