title: Bromodomain and extraterminal proteins suppress NF-E2-related factor 2-mediated antioxidant gene expression.
abstract: Oxidative stress, a pathogenetic factor in many conditions, including chronic obstructive pulmonary disease, arises due to accumulation of reactive oxygen species and defective antioxidant defenses in the lungs. The latter is due, at least in part, to impaired activation of NF-E2-related factor 2 (Nrf2), a transcription factor involved in the activation of antioxidant and cytoprotective genes. The bromodomain and extraterminal (BET) proteins, Brd2, Brd3, Brd4, and BrdT, bind to acetylated lysine residues on histone or nonhistone proteins recruiting transcriptional regulators and thus activating or repressing gene transcription. We investigated whether BET proteins modulate the regulation of Nrf2-dependent gene expression in primary human airway smooth muscle cells and the human monocytic cell line, THP-1. Inhibition of BET protein bromodomains using the inhibitor JQ1+ or attenuation of Brd2 and Brd4 expression using small interfering RNA led to activation of Nrf2-dependent transcription and expression of the antioxidant proteins heme oxygenase-1, NADPH quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit. Also, JQ1+ prevented H2O2-induced intracellular reactive oxygen species production. By coimmunoprecipitation, BET proteins were found to be complexed with Nrf2, whereas chromatin-immunoprecipitation studies indicated recruitment of Brd2 and Brd4 to Nrf2-binding sites on the promoters of heme oxygenase-1 and NADPH quinone oxidoreductase 1. BET proteins, particularly Brd2 and Brd4, may play a key role in the regulation of Nrf2-dependent antioxidant gene transcription and are hence an important target for augmenting antioxidant responses in oxidative stress-mediated diseases.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mercado
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Clarke
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Bhavsar
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000276:immunology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002868:Chromosomal Proteins, Non-Histone; D051547:Heme Oxygenase-1; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D016877:Oxidants; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C518475:BRDT protein, mouse; D000092468:Bromodomain Containing Proteins; C490844:Brd2 protein, mouse; C518476:Brd3 protein, mouse; C486694:Brd4 protein, mouse; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; C447479:NQO1 protein, human
references.citation: Nat Rev Cancer. 2012 Jun 22;12(7):465-77
references.pmid: 22722403
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jul 15;305(2):L165-74
references.pmid: 23686858
references.citation: FASEB J. 2009 Sep;23(9):2810-9
references.pmid: 19376817
references.citation: Mol Cell Biochem. 2011 Jan;346(1-2):31-7
references.pmid: 20842520
references.citation: Cancer Res. 2008 Jan 15;68(2):364-8
references.pmid: 18199529
references.citation: Biochem Biophys Res Commun. 2011 Mar 11;406(2):292-8
references.pmid: 21320471
references.citation: Mol Cell Biol. 2002 May;22(9):2883-92
references.pmid: 11940647
references.citation: Nature. 2011 Aug 03;478(7370):524-8
references.pmid: 21814200
references.citation: Int J Hematol. 2012 Oct;96(4):428-37
references.pmid: 23054645
references.citation: Biochimie. 2013 Mar;95(3):585-94
references.pmid: 23274128
references.citation: Nature. 2010 Dec 23;468(7327):1067-73
references.pmid: 20871596
references.citation: J Proteome Res. 2006 Mar;5(3):502-11
references.pmid: 16512664
references.citation: Mol Cell. 2005 Aug 19;19(4):535-45
references.pmid: 16109377
references.citation: J Mol Cell Cardiol. 2013 Oct;63:175-9
references.pmid: 23939492
references.citation: FASEB J. 2001 Apr;15(6):1110-2
references.pmid: 11292684
references.citation: Proc Am Thorac Soc. 2005;2(4):347-54; discussion 371-2
references.pmid: 16267361
references.citation: Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
references.pmid: 9240432
references.citation: Atherosclerosis. 2010 Dec;213(2):377-84
references.pmid: 20864107
references.citation: Mol Cell Biol. 2011 Jul;31(13):2641-52
references.pmid: 21555454
references.citation: Dev Dyn. 2009 Apr;238(4):908-17
references.pmid: 19301389
references.citation: Mol Cell. 2005 Aug 19;19(4):523-34
references.pmid: 16109376
references.citation: Am J Respir Cell Mol Biol. 2008 Dec;39(6):673-82
references.pmid: 18566336
references.citation: J Biol Chem. 2003 Jun 13;278(24):21592-600
references.pmid: 12682069
references.citation: Biochem J. 2009 Dec 14;425(1):71-83
references.pmid: 19883376
references.citation: J Biol Chem. 2007 May 4;282(18):13141-5
references.pmid: 17329240
references.citation: Mol Cell Biol. 2005 May;25(10):4150-65
references.pmid: 15870285
references.citation: Mol Cell. 2008 Apr 11;30(1):51-60
references.pmid: 18406326
references.citation: Mol Cell Biol. 2009 May;29(10):2658-72
references.pmid: 19273602
references.citation: Eur Respir J. 2006 Jul;28(1):219-42
references.pmid: 16816350
references.citation: PLoS One. 2010 Jan 05;5(1):e8579
references.pmid: 20062804
references.citation: Expert Rev Mol Med. 2011 Sep 13;13:e29
references.pmid: 21933453
references.citation: Sci Signal. 2010 Mar 09;3(112):re3
references.pmid: 20215646
references.citation: J Biol Chem. 2005 Apr 29;280(17):16891-900
references.pmid: 15734732
references.citation: Thorax. 2008 Oct;63(10):916-24
references.pmid: 18559366
references.citation: Cancer Res. 2013 May 15;73(10):3097-108
references.pmid: 23612120
references.citation: Am J Respir Crit Care Med. 2008 Sep 15;178(6):592-604
references.pmid: 18556627
references.citation: J Biochem Mol Toxicol. 2008 Feb;22(1):63-76
references.pmid: 18273910
references.citation: Nat Rev Immunol. 2008 Mar;8(3):183-92
references.pmid: 18274560
references.citation: J Virol. 2011 Nov;85(22):11752-69
references.pmid: 21900162
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1543-55
references.pmid: 17369289
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):E2949-55
references.pmid: 23045680
references.citation: Mol Cell Biol. 2008 Feb;28(3):967-76
references.pmid: 18039861