Universität zu Köln

Hussong, M., Boerno, S. T., Kerick, M., Wunderlich, A., Franz, A., Sueltmann, H., Timmermann, B., Lehrach, H., Hirsch-Kauffmann, M. and Schweiger, M. R. (2014). The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response. Cell Death Dis., 5. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hussong, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boerno, S. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kerick, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Franz, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sueltmann, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmermann, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehrach, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirsch-Kauffmann, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, M. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-442037
DOI:	10.1038/cddis.2014.157
Journal or Publication Title:	Cell Death Dis.
Volume:	5
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEME OXYGENASE-1 GENE; TRANSCRIPTION FACTOR; SELECTIVE-INHIBITION; INDUCIBLE EXPRESSION; SUPER-ENHANCERS; PROSTATE-CANCER; FANCONI-ANEMIA; KEAP1 GENE; P-TEFB; NRF2 Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44203