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

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