AccScience Publishing / GTM / Volume 2 / Issue 3 / DOI: 10.36922/gtm.1442
Cite this article
112
Download
928
Views
Journal Browser
Volume | Year
Issue
Search
News and Announcements
View All
REVIEW

Essential roles of BRD4 in cancer: DNA damage, transcription regulation, and signal transduction

Sylvia Y. Sun1,2*
Show Less
1 Mortimer B. Zuckerman Research Center - Sloan Kettering Institute, 417 E 68th Street, New York, United States of America
2 Department of Dental, New York University, 345 E. 24th Street, New York, United States of America
Global Translational Medicine 2023, 2(3), 1442 https://doi.org/10.36922/gtm.1442
Submitted: 2 August 2023 | Accepted: 22 September 2023 | Published: 29 September 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

During cancer progression, bromodomain and extra-terminal (BET) families regulate chromatin and recruit enzymes that are associated with chromatin regulation to control gene expression. The bromodomain-containing protein 4 (BRD4) plays an important role in DNA damage repair, nuclear factor kappa B (NFκB) signaling, interaction with c-Myc, and transcription regulation of genes essential in carcinogenesis, as well as links transcription at enhancers and genes to regulate enhancer transcription. The colocalization of BRD4 with enhancer and promoter-proximal gene regions enables the elongation activation at enhancer genes. The inactivation of BRD4 has been demonstrated to inhibit cancer development, corroborating BRD4 as a promising therapeutic target. In addition, small-molecule inhibitors targetting functional domains of BRD4 are under investigation for their potential therapeutic applications in cancer and other diseases. This review presents an overview of BRD4 function and its dysfunction in cancer progression, as well as discusses how the potential of BRD4 as a therapeutic target.

Keywords
BRD4 signaling
Therapy
Cancer
Funding
None.
References
  1. Deeney JT, Belkina AC, Shirihai OS, et al., 2016, BET bromodomain proteins Brd2, Brd3 and Brd4 selectively regulate metabolic pathways in the pancreatic β-cell. PLoS One, 11: e0151329. https://doi.org/10.1371/journal.pone.0151329

 

  1. Marazzi I, Greenbaum BD, Low DH, et al., 2018, Chromatin dependencies in cancer and inflammation. Nat Rev Mol Cell Biol, 19: 245–261. https://doi.org/10.1038/nrm.2017.11

 

  1. Jones MH, Numata M, Shimane M, 1997, Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics, 45: 529–534. https://doi.org/10.1006/geno.1997.5000

 

  1. Shang E, Nickerson HD, Wen D, et al., 2007, The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development, 134: 3507–3515. https://doi.org/10.1242/dev.004481

 

  1. Zhou Q, Li T, Price DH, 2012, RNA polymerase II elongation control. Annu Rev Biochem, 81: 119–143. https://doi.org/10.1146/annurev-biochem-052610-095910

 

  1. French CA, 2016, Small-molecule targeting of BET proteins in cancer. Adv Cancer Res, 131: 21–58. https://doi.org/10.1016/bs.acr.2016.04.001

 

  1. Liu Z, Wang P, Chen H, et al., 2017, Drug discovery targeting bromodomain-containing protein 4. J Med Chem, 60: 4533– 4558. https://doi.org/10.1021/acs.jmedchem.6b01761

 

  1. Bradner JE, Hnisz D, Young RA, 2017, Transcriptional addiction in cancer. Cell, 168: 629–643. https://doi.org/10.1016/j.cell.2016.12.013

 

  1. Lori L, Pasquo A, Lori C, et al., 2016, Effect of BET missense mutations on bromodomain function, inhibitor binding and stability. PLoS One, 11: e0159180. https://doi.org/10.1371/journal.pone.0159180

 

  1. Wu SY, Chiang CM, 2007, The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem, 282: 13141–13145. https://doi.org/10.1074/jbc.R700001200

 

  1. Devaiah BN, Gegonne A, Singer DS, 2016, Bromodomain 4: A cellular Swiss army knife. J Leukoc Biol, 100: 679–686. https://doi.org/10.1189/jlb.2RI0616-250R

 

  1. Devaiah BN, Case-Borden C, Gegonne A, et al., 2016, BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin. Nat Struct Mol Biol, 23: 540–548. https://doi.org/10.1038/nsmb.3228

 

  1. Malvezzi F, Stubbs CJ, Jowitt TA, et al., 2021, Phosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins. Commun Biol, 4: 1273. https://doi.org/10.1038/s42003-021-02750-6

 

  1. Devaiah BN, Mu J, Akman B, et al., 2020, MYC protein stability is negatively regulated by BRD4. Proc Natl Acad Sci U S A, 117: 13457–13467. https://doi.org/10.1073/pnas.1919507117

 

  1. Dey A, Ellenberg J, Farina A, et al., 2000, A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol, 20: 6537–6549. https://doi.org/10.1128/MCB.20.17.6537-6549.2000

 

  1. Dey A, Nishiyama A, Karpova T, et al., 2009, Brd4 Marks select genes on mitotic chromatin and directs Postmitotic transcription. Mol Biol Cell, 20: 4899–4909. https://doi.org/10.1091/mbc.e09-05-0380

 

  1. Mochizuki K, Nishiyama A, Jang MK, et al., 2008, The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem, 283: 9040–9048. https://doi.org/10.1074/jbc.M707603200

 

  1. Yang ZY, He N, Zhou Q, 2008, Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol, 28: 967–976. https://doi.org/10.1128/MCB.01020-07

 

  1. Di Micco R, Fontanals-Cirera B, Low V, et al., 2014, Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep, 9: 234–247. https://doi.org/10.1016/j.celrep.2014.08.055

 

  1. Liu W, Stein P, Cheng X, et al., 2014, BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. Cell Death Differ, 21: 1950–1660. https://doi.org/10.1038/cdd.2014.124

 

  1. Wu T, Pinto HB, Kamikawa YF, et al., 2015, The BET family member BRD4 interacts with OCT4 and regulates pluripotency gene expression. Stem Cell Reports, 4: 390–403. https://doi.org/10.1016/j.stemcr.2015.01.012

 

  1. Houzelstein D, Bullock SL, Lynch DE, et al., 2002, Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol Cell Biol, 22: 3794–3802. https://doi.org/10.1128/MCB.22.11.3794-3802.2002

 

  1. Lee JE, Park YK, Park S, et al., 2017, Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. Nat Commun, 8: 2217. https://doi.org/10.1038/s41467-017-02403-5

 

  1. Drumond-Bock AL, Bieniasz M, 2021, The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis. Mol Cancer, 20: 145. https://doi.org/10.1186/s12943-021-01424-5

 

  1. Shi J, Vakoc CR, 2014, The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell, 54: 728–736. https://doi.org/10.1016/j.molcel.2014.05.016

 

  1. Wu SY, Lee AY, Hou SY, et al, 2006, Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev, 20: 2383–2396. https://doi.org/10.1101/gad.1448206

 

  1. Karr JP, Ferrie JJ, Tjian R, et al., 2021, The transcription factor activity gradient (TAG) model: Contemplating a contact-independent mechanism for enhancer-promoter communication. Gene Dev, 36: 7–16. https://doi.org/10.1101/gad.349160.121

 

  1. Winter GE, Mayer A, Buckley DL, et al., 2017, BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Mol Cell, 67: 5–18.e19. https://doi.org/10.1016/j.molcel.2017.06.00

 

  1. Rahnamoun H, Lee J, Sun Z, et al., 2018, RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation. Nat Struct Mol Biol, 25: 687–697. https://doi.org/10.1038/s41594-018-0102-0

 

  1. Bressin A, Jasnovidova O, Arnold M, et al., 2023, High-sensitive nascent transcript sequencing reveals BRD4- specific control of widespread enhancer and target gene transcription. Nat Commun, 14: 4971. https://doi.org/10.1038/s41467-023-40633-y

 

  1. Mani RS, Chinnaiyan AM, 2010, Triggers for genomic rearrangements: Insights into genomic, cellular and environmental influences. Nat Rev Genet, 11: 819–829. https://doi.org/10.1038/nrg2883

 

  1. Misteli T, Soutoglou E, 2009, The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat Rev Mol Cell Biol, 10: 243–254. https://doi.org/10.1038/nrm2651

 

  1. Stanlie A, Yousif AS, Akiyama H, et al., 2014, Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining. Mol Cell, 55: 97–110. https://doi.org/10.1016/j.molcel.2014.05.018

 

  1. Li X, Baek G, Ramanand SG, et al., 2018, BRD4 promotes DNA repair and mediates the formation of TMPRSS2-ERG gene rearrangements in prostate cancer. Cell Rep, 22: 796–808. https://doi.org/10.1016/j.celrep.2017.12.078

 

  1. Schultz LB, Chehab NH, Malikzay A, et al., 2000, p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol, 151: 1381–1390. https://doi.org/10.1083/jcb.151.7.1381

 

  1. Wang B, Matsuoka S, Carpenter PB, et al., 2002, 53BP1, a mediator of the DNA damage checkpoint. Science, 298: 1435–1438. https://doi.org/10.1126/science.1076182

 

  1. Sabari BR, Dall’Agnese A, Boija A, et al., 2018, Coactivator condensation at super-enhancers links phase separation and gene control. Science, 361: eaar3958. https://doi.org/10.1126/science.aar3958

 

  1. Floyd SR, Pacold ME, Huang Q, et al., 2013, The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature, 498: 246–225. https://doi.org/10.1038/nature12147

 

  1. Zhang J, Dulak AM, Hattersley MM, et al., 2018, BRD4 facilitates replication stress-induced DNA damage response. Oncogene, 37: 3763–3777. https://doi.org/10.1038/s41388-018-0194-3

 

  1. Zeman MK, Cimprich KA, 2014, Causes and consequences of replication stress. Nat Cell Biol, 16: 2–9. https://doi.org/10.1038/ncb2897

 

  1. Zhou BB, Bartek J, 2004, Targeting the checkpoint kinases: Chemosensitization versus chemoprotection. Nat Rev Cancer, 4: 216–225. https://doi.org/10.1038/nrc1296

 

  1. Gelot C, Magdalou I, Lopez BS, 2015, Replication stress in mammalian cells and its consequences for mitosis. Genes (Basel), 6: 267–298. https://doi.org/10.3390/genes6020267

 

  1. Cheung-Ong K, Giaever G, Nislow C, 2013, DNA-damaging agents in cancer chemotherapy: Serendipity and chemical biology. Chem Biol, 20: 648–659. https://doi.org/10.1016/j.chembiol.2013.04.007

 

  1. Ledermann JA, Harter P, Gourley C, et al., 2016, Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: An updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol, 17: 1579–1589. https://doi.org/10.1016/S1470-2045(16)30376-X

 

  1. Ledermann JA, Harter P, Gourley C, et al., 2016, Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol, 34: 5501. https://doi.org/10.1200/JCO.2016.34.15_suppl.5501

 

  1. Zimmer AS, Gillard M, Lipkowitz S, et al., 2018, Update on PARP inhibitors in breast cancer. Curr Treat Options Oncol, 19: 21. https://doi.org/10.1007/s11864-018-0540-2

 

  1. Sun CY, Yin J, Fang Y, et al., 2018, BRD4 inhibition is synthetic lethal with PARP inhibitors through the induction of homologous recombination deficiency. Cancer Cell, 33: 401–416.e8. https://doi.org/10.1016/j.ccell.2018.01.019

 

  1. Donati B, Lorenzini E, Ciarrocchi A, 2018, BRD4 and cancer: Going beyond transcriptional regulation. Mol Cancer, 17: 164. https://doi.org/10.1186/s12943-018-0915-9

 

  1. Gee ME, Faraahi Z, McCormick A, et al., 2018, DNA damage repair in ovarian cancer: Unlocking the heterogeneity. J Ovarian Res, 11: 50. https://doi.org/10.1186/s13048-018-0424-x

 

  1. Dey A, Chitsaz F, Abbasi A, et al., 2003, The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A, 100: 8758–8763. https://doi.org/10.1073/pnas.1433065100

 

  1. Choi S, Bakkenist CJ, 2013, Brd4 shields chromatin from ATM kinase signaling storms. Sci Signal, 6: pe30. https://doi.org/10.1126/scisignal.2004622

 

  1. Rodriguez RM, Huidobro C, Urdinguio RG, et al., 2012, Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer. J Mol Med (Berl), 90: 587–595. https://doi.org/10.1007/s00109-011-0837-0

 

  1. Filippakopoulos P, Knapp S, 2014, Targeting bromodomains: Epigenetic readers of lysine acetylation. Nat Rev Drug Discov, 13: 337–356. https://doi.org/10.1038/nrd4286

 

  1. Brasier AR, Tian B, Jamaluddin M, et al., 2011, RelA Ser276 phosphorylation-coupled Lys310 acetylation controls transcriptional elongation of inflammatory cytokines in respiratory syncytial virus infection. J Virol, 85: 11752–11769. https://doi.org/10.1128/JVI.05360-11

 

  1. Zou Z, Huang B, Wu X, et al., 2014, Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene, 33: 2395–2404. https://doi.org/10.1038/onc.2013.179

 

  1. Lee H, Herrmann A, Deng JH, et al., 2009, Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell, 15: 283–293. https://doi.org/10.1016/j.ccr.2009.02.015

 

  1. Levy D, Kuo AJ, Chang Y, et al., 2011, Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling. Nat Immunol, 12: 29–36. https://doi.org/10.1038/ni.1968

 

  1. Chapuy B, McKeown MR, Lin CY, et al., 2013, Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell, 24: 777–790. https://doi.org/10.1016/j.ccr.2013.11.003

 

  1. Delmore JE, Issa GC, Lemieux ME, et al., 2011, BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 146: 904–917. https://doi.org/10.1016/j.cell.2011.08.017

 

  1. Gröschel S, Sanders MA, Hoogenboezem R, et al., 2014, A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell, 157: 369–381. https://doi.org/10.1016/j.cell.2014.02.019

 

  1. Glodzik D, Morganella S, Davies H, et al., 2017, A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nat Genet, 49: 341–348. https://doi.org/10.1038/ng.3771

 

  1. Dang CV, O’Donnell KA, Zeller KI, et al., 2006, The c-Myc target gene network. Semin Cancer Biol, 16: 253–264. https://doi.org/10.1016/j.semcancer.2006.07.014

 

  1. Filippakopoulos P, Qi J, Picaud S, et al., 2010, Selective inhibition of BET bromodomains. Nature, 468: 1067–1073. https://doi.org/10.1038/nature09504

 

  1. Nicodeme E, Jeffrey KL, Schaefer U, et al., 2010, Suppression of inflammation by a synthetic histone mimic. Nature, 468: 1119–1123. https://doi.org/10.1038/nature09589

 

  1. Mertz JA, Conery AR, Bryant BM, et al., 2011, Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A, 108: 16669–16674. https://doi.org/10.1073/pnas.1108190108

 

  1. Ding D, Zheng R, Tian Y, et al., 2022, Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer. Nat Commun, 13: 6311. https://doi.org/10.1038/s41467-022-34024-y

 

  1. Weintraub SJ, Prater CA, Dean DC, 1992, Retinoblastoma protein switches the E2F site from positive to negative element. Nature, 358: 259–261. https://doi.org/10.1038/358259a0

 

  1. Jin X, Ding D, Yan Y, et al., 2019, Phosphorylated RB promotes cancer immunity by inhibiting NF-κB activation and PD-L1 expression. Mol Cell, 73: 22–35.e6. https://doi.org/10.1016/j.molcel.2018.10.034

 

  1. Hassler M, Singh S, Yue WW, et al., 2007, Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell, 28: 371–385. https://doi.org/10.1016/j.molcel.2007.08.023

 

  1. Liu, N, Ling R, Tang X, et al., 2022, Post-translational modifications of BRD4: Therapeutic targets for tumor. Front Oncol, 12: 847701. https://doi.org/10.3389/fonc.2022.847701

 

  1. Dai X, Gan W, Li X, et al., 2017, Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med, 23: 1063–1071. https://doi.org/10.1038/nm.4378

 

  1. Janouskova H, El Tekle G, Bellini E, et al., 2017, Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat Med, 23: 1046–1054. https://doi.org/10.1038/nm.4372

 

  1. Jin X, Yan Y, Wang D, et al., 2018, DUB3 promotes BET inhibitor resistance and cancer progression by deubiquitinating Brd4. Mol Cell, 71: 592–605.e4. https://doi.org/10.1016/j.molcel.2018.06.036

 

  1. Zhang P, Wang D, Zhao Y, et al., 2017, Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med, 23: 1055–1062. https://doi.org/10.1038/nm.4379

 

  1. Wang W, Tang Y, Xiao Q, et al., 2021, Stromal induction of BRD4 phosphorylation results in chromatin remodeling and BET inhibitor resistance in colorectal cancer. Nat Commun, 12: 4441. https://doi.org/10.1038/s41467-021-24687-4

 

  1. Garnier JM, Sharp PP, Burns CJ, 2014, BET bromodomain inhibitors: A patent review. Expert Opin Ther Pat, 24: 185– 199. https://doi.org/10.1517/13543776.2014.859244

 

  1. Rahman S, Sowa ME, Ottinger M, et al., 2011, The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol, 31: 2641–2652. https://doi.org/10.1128/MCB.01341

 

  1. Chaidos A, Caputo V, Gouvedenou K, et al., 2014, Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood, 123: 697–705. https://doi.org/10.1182/blood-2013-01-478420

 

  1. Wyce A, Degenhardt Y, Bai Y, et al., 2013, Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget, 4: 2419–2429. https://doi.org/10.18632/oncotarget.1572

 

  1. Riveiro ME, Astorgues-Xerri L, Vazquez R, et al., 2016, OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations. Oncotarget, 7: 84675–84687. https://doi.org/10.18632/oncotarget.13181

 

  1. Tontsch-Grunt U, Traexler PE, Baum A, et al., 2022, Therapeutic impact of BET inhibitor BI 894999 treatment: Backtranslation from the clinic. Br J Cancer, 127: 577–586. https://doi.org/10.1038/s41416-022-01815-5
Conflict of interest
The author declares no conflict of interest.
Share
Back to top
Global Translational Medicine, Electronic ISSN: 2811-0021 Published by AccScience Publishing