Down-regulation of NF-κB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition

Zhang, Guangtao; Liu, Ruijie; Zhong, Yifei; Plotnikov, A.N.; Zhang, Weijia; Zeng, Lei; Rusinova, E. V.; Gerona-Nevarro, Guillermo; Moshkina, Natasha; Joshua, Jennifer; Chuang, Peter Y.; Ohlmeyer, Michael; He, John Cijiang; Zhou, Ming‐Ming

doi:10.1074/jbc.m112.359505

Cited by 181 publications

(201 citation statements)

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“…Its pro-inflammatory activity is dependent on the association between its acetylated lysine 310 and BRD4 in complex with pTEFb and RNA polymerase II, which form an active transcription complex (Huang et al, 2009). Analysis of our data proves that BRD4 uncoupling from NF-κB promoter is associated with down-regulation of pro-inflammatory cytokine expression, which agrees with previous reports (Nicodeme et al, 2010;G Zhang et al, 2012). Moreover, the NF-κB downstream transcription factors, c-Fos and NFATc1, are involved in RANKLinduced osteoclastogenesis.…”

Section: Discussionsupporting

confidence: 90%

BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction

et al. 2014

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BET proteins are a group of epigenetic regulators controlling transcription through reading acetylated histone tails and recruiting transcription complexes. They are considered as potential therapeutic targets in many distinct diseases. A novel synthetic bromodomain and extraterminal domain (BET) inhibitor, JQ1, was proved to suppress oncogene transcription and inflammatory responses. The present study was aimed to investigate the effects of JQ1 on inflammatory response and bone destruction in experimental periodontitis. We found that JQ1 significantly suppressed lipopolysaccharide (LPS)-stimulated inflammatory cytokine transcription, including interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), as well as receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast markers, such as c-Fos, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K in vitro. JQ1 also inhibited toll-like receptors 2/4 (TLR2/4) expression and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Chromatin immunoprecipitation and quantitative polymerase chain reaction (ChIP-qPCR) revealed that JQ1 neutralized BRD4 enrichment at several gene promoter regions, including NF-κB, TNF-α, c-Fos, and NFATc1. In a murine periodontitis model, systemic administration of JQ1 significantly inhibited inflammatory cytokine expression in diseased gingival tissues. Alveolar bone loss was alleviated in JQ1-treated mice because of reduced osteoclasts in periodontal tissues. These unprecedented results suggest the BET inhibitor JQ1 as a prospective new approach for treating periodontitis.

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Section: Discussionsupporting

confidence: 90%

BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction

et al. 2014

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“…As a member of the bromodomain and extraterminal domain (BET) family of proteins, Brd4 contains tandem bromodomains, BD1 and BD2, which bind to acetylated lysine residues on diverse proteins, and also harbors an extraterminal domain at the carboxy end that recruits P-TEFb. Brd4 exploits diverse tethers to recruit P-TEFb to transcribable chromatin: acetylated H3 and H4 histones, the Mediator complex, or particular nonhistone proteins; notably, NF-κB (20,21), p53 (22), and Twist (23). Our findings argue that Brd4, recruited in response to an orchestrated series of posttranslational modifications of Aire's CARD, bridges Aire and P-TEFb to release promoter-proximal Pol-II pausing and induce transcription of a broad swath of genes.…”

Section: Significancementioning

confidence: 82%

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida

Bansal

Schaefer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomaincontaining protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.

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“…However, other possible mechanisms, not probed here, may also be contributing toward the superior outcome. BRD4 has also been shown to bind to the acetylated lysine-310 of the RelA subunit of NF-kB and regulate its transcriptional activity (32,33). By inducing RelA acetylation, panobinostat treatment may also increase the BRD4 dependency of the NF-kB activity in AML cells.…”

Section: Discussionmentioning

confidence: 99%

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

172

170

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The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1cþ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34 þ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142-54. Ó2014 AACR.

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Down-regulation of NF-κB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition

Cited by 181 publications

References 50 publications

BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction

BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

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