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Cell Death Dis. 2014 Apr 24;5:e1195. doi: 10.1038/cddis.2014.157.

The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.

Author information

  • 11] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Department of Biology, Chemistry and Pharmacy, Free University, Berlin, Germany.
  • 2Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 3Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 4Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 51] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Cologne Center for Genomics, University of Cologne, Cologne, Germany.

Abstract

The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti-cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress.

PMID:
24763052
PMCID:
PMC4001311
DOI:
10.1038/cddis.2014.157
[PubMed - indexed for MEDLINE]
Free PMC Article
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