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

M Hussong1, S T Börno2, M Kerick2

  • 11] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Department of Biology, Chemistry and Pharmacy, Free University, Berlin, Germany.

Cell Death & Disease
|April 26, 2014
PubMed

Insights

Bromodomain protein 4 (BRD4) regulates oxidative stress response genes in cancer. Inhibiting BRD4 reduces reactive oxygen species (ROS) and enhances cell survival, revealing BRD4

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Molecular Oncology

Background:

  • Bromodomain protein 4 (BRD4) is an epigenetic regulator and a promising anti-cancer target.
  • BRD4's role in regulating transcriptional networks, particularly in cancer, requires further elucidation.
  • Understanding BRD4's impact on cellular stress responses is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the transcriptional effects of BRD4 in cancer.
  • To identify key BRD4-regulated genes involved in oxidative stress pathways.
  • To explore the functional consequences of BRD4 modulation on cancer cell response to oxidative stress.

Main Methods:

  • Generation of BRD4 knockdown cell expression signatures using RNA-Sequencing.
  • Integration of RNA-Seq data with BRD4 chromatin immunoprecipitation (ChIP) sequencing data.
  • Correlation analysis of BRD4 target genes with gene expression data from human prostate cancers.
  • Assessment of reactive oxygen species (ROS) production and cell viability under hydrogen peroxide (H2O2) exposure following BRD4 knockdown or inhibition.
  • Analysis of the KEAP1/NRF2 axis and heme oxygenase 1 (HMOX1) regulation.

Main Results:

  • BRD4 knockdown enriched for oxidative stress response genes, including KEAP1, SESN3, and HDAC6.
  • BRD4 inhibition (using JQ1) or knockdown decreased ROS production and increased cell viability under H2O2 exposure.
  • BRD4 deregulation disrupted the KEAP1/NRF2 axis and impaired the regulation of HMOX1.
  • BRD4 was found to directly target the HMOX1 promoter, independent of exogenous stress induction.

Conclusions:

  • BRD4 acts as a key transcriptional regulator of oxidative stress response genes in cancer.
  • Targeting BRD4 modulates cellular redox balance and impacts cancer cell survival under stress.
  • BRD4 is identified as a critical signal transducer in the cellular response to oxidative stress, offering therapeutic potential.

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