The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.
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.
1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Department of Biology, Chemistry and Pharmacy, Free University, Berlin, Germany.
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Hussong
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Börno
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Kerick
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Wunderlich
1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Department of Biology, Chemistry and Pharmacy, Free University, Berlin, Germany.
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Franz
Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Sültmann
Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Timmermann
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Lehrach
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Hirsch-Kauffmann
1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Cologne Center for Genomics, University of Cologne, Cologne, Germany.
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Schweiger
D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D059372:Nucleotide Motifs / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D051547:Heme Oxygenase-1; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C431364:KEAP1 protein, human; C007095:cobaltiprotoporphyrin