BRD4 as a Therapeutic Target in Pulmonary Diseases
Abstract
:1. Introduction
2. Implications of BET Proteins in Pulmonary Diseases
2.1. Acute Lung Inflammation
2.2. Asthma
2.3. Pulmonary Artery Hypertension (PAH)
2.4. Pulmonary Fibrosis
2.5. Chronic Obstructive Pulmonary Disease (COPD)
3. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Yang, Z.; Yik, J.H.; Chen, R.; He, N.; Jang, M.K.; Ozato, K.; Zhou, Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 2005, 19, 535–545. [Google Scholar] [CrossRef]
- Jang, M.K.; Mochizuki, K.; Zhou, M.; Jeong, H.S.; Brady, J.N.; Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 2005, 19, 523–534. [Google Scholar] [CrossRef]
- Rahman, S.; Sowa, M.E.; Ottinger, M.; Smith, J.A.; Shi, Y.; Harper, J.W.; Howley, P.M. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol. Cell. Biol. 2011, 31, 2641–2652. [Google Scholar] [CrossRef]
- Han, F.; Zhang, L.; Chen, C.; Wang, Y.; Zhang, Y.; Qian, L.; Sun, W.; Zhou, D.; Yang, B.; Zhang, H.; et al. GLTSCR1 Negatively Regulates BRD4-Dependent Transcription Elongation and Inhibits CRC Metastasis. Adv. Sci. 2019, 6, 1901114. [Google Scholar] [CrossRef]
- Liu, W.; Ma, Q.; Wong, K.; Li, W.; Ohgi, K.; Zhang, J.; Aggarwal, A.; Rosenfeld, M.G. Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell 2013, 155, 1581–1595. [Google Scholar] [CrossRef]
- Houzelstein, D.; Bullock, S.L.; Lynch, D.E.; Grigorieva, E.F.; Wilson, V.A.; Beddington, R.S. Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol. Cell. Biol. 2002, 22, 3794–3802. [Google Scholar] [CrossRef]
- Gyuris, A.; Donovan, D.J.; Seymour, K.A.; Lovasco, L.A.; Smilowitz, N.R.; Halperin, A.L.; Klysik, J.E.; Freiman, R.N. The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis. Biochim. Biophys. Acta 2009, 1789, 413–421. [Google Scholar] [CrossRef]
- Shi, J.; Vakoc, C.R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell 2014, 54, 728–736. [Google Scholar] [CrossRef]
- Huang, B.; Yang, X.D.; Zhou, M.M.; Ozato, K.; Chen, L.F. Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol. Cell. Biol. 2009, 29, 1375–1387. [Google Scholar] [CrossRef]
- Lee, J.E.; Park, Y.K.; Park, S.; Jang, Y.; Waring, N.; Dey, A.; Ozato, K.; Lai, B.; Peng, W.; Ge, K. Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. Nat. Commun. 2017, 8, 2217. [Google Scholar] [CrossRef]
- Mann, M.; Roberts, D.S.; Zhu, Y.; Li, Y.; Zhou, J.; Ge, Y.; Brasier, A.R. Discovery of RSV-Induced BRD4 Protein Interactions Using Native Immunoprecipitation and Parallel Accumulation-Serial Fragmentation (PASEF) Mass Spectrometry. Viruses 2021, 13, 454. [Google Scholar] [CrossRef] [PubMed]
- Uppal, S.; Gegonne, A.; Chen, Q.; Thompson, P.S.; Cheng, D.; Mu, J.; Meerzaman, D.; Misra, H.S.; Singer, D.S. The Bromodomain Protein 4 Contributes to the Regulation of Alternative Splicing. Cell Rep. 2019, 29, 2450–2460.e5. [Google Scholar] [CrossRef] [PubMed]
- Hussong, M.; Kaehler, C.; Kerick, M.; Grimm, C.; Franz, A.; Timmermann, B.; Welzel, F.; Isensee, J.; Hucho, T.; Krobitsch, S.; et al. The bromodomain protein BRD4 regulates splicing during heat shock. Nucleic Acids Res. 2017, 45, 382–394. [Google Scholar] [CrossRef]
- Mann, M.W.; Fu, Y.; Gearhart, R.L.; Xu, X.; Roberts, D.S.; Li, Y.; Zhou, J.; Ge, Y.; Brasier, A.R. Bromodomain-containing Protein 4 regulates innate inflammation via modulation of alternative splicing. Front. Immunol. 2023, 14, 1212770. [Google Scholar] [CrossRef] [PubMed]
- Gilan, O.; Rioja, I.; Knezevic, K.; Bell, M.J.; Yeung, M.M.; Harker, N.R.; Lam, E.Y.N.; Chung, C.W.; Bamborough, P.; Petretich, M.; et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science 2020, 368, 387–394. [Google Scholar] [CrossRef] [PubMed]
- Shorstova, T.; Foulkes, W.D.; Witcher, M. Achieving clinical success with BET inhibitors as anti-cancer agents. Br. J. Cancer 2021, 124, 1478–1490. [Google Scholar] [CrossRef]
- Xu, Y.; Vakoc, C.R. Targeting Cancer Cells with BET Bromodomain Inhibitors. Cold Spring Harb. Perspect. Med. 2017, 7, a026674. [Google Scholar] [CrossRef]
- Belkina, A.C.; Denis, G.V. BET domain co-regulators in obesity, inflammation and cancer. Nat. Rev. Cancer 2012, 12, 465–477. [Google Scholar] [CrossRef]
- Stathis, A.; Bertoni, F. BET Proteins as Targets for Anticancer Treatment. Cancer Discov. 2018, 8, 24–36. [Google Scholar] [CrossRef]
- Sarnik, J.; Poplawski, T.; Tokarz, P. BET Proteins as Attractive Targets for Cancer Therapeutics. Int. J. Mol. Sci. 2021, 22, 11102. [Google Scholar] [CrossRef]
- Chen, K.; Campfield, B.T.; Wenzel, S.E.; McAleer, J.P.; Kreindler, J.L.; Kurland, G.; Gopal, R.; Wang, T.; Chen, W.; Eddens, T.; et al. Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation. JCI Insight. 2016, 1, e87168. [Google Scholar] [CrossRef]
- Huang, M.; Zeng, S.; Zou, Y.; Shi, M.; Qiu, Q.; Xiao, Y.; Chen, G.; Yang, X.; Liang, L.; Xu, H. The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-kappaB and MAPK activation. Br. J. Pharmacol. 2017, 174, 101–115. [Google Scholar] [CrossRef]
- Jahagirdar, R.; Attwell, S.; Marusic, S.; Bendele, A.; Shenoy, N.; McLure, K.G.; Gilham, D.; Norek, K.; Hansen, H.C.; Yu, R.; et al. RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease. Mol. Pharmacol. 2017, 92, 694–706. [Google Scholar] [CrossRef]
- Liu, Z.; Tian, B.; Chen, H.; Wang, P.; Brasier, A.R.; Zhou, J. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. Eur. J. Med. Chem. 2018, 151, 450–461. [Google Scholar] [CrossRef]
- Gordon, D.E.; Jang, G.M.; Bouhaddou, M.; Xu, J.; Obernier, K.; White, K.M.; O’Meara, M.J.; Rezelj, V.V.; Guo, J.Z.; Swaney, D.L.; et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020, 583, 459–468. [Google Scholar] [CrossRef]
- Qiao, Y.; Wang, X.M.; Mannan, R.; Pitchiaya, S.; Zhang, Y.; Wotring, J.W.; Xiao, L.; Robinson, D.R.; Wu, Y.M.; Tien, J.C.; et al. Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Proc. Natl. Acad. Sci. USA 2021, 118, e2021450118. [Google Scholar] [CrossRef]
- Chen, I.P.; Longbotham, J.E.; McMahon, S.; Suryawanshi, R.K.; Khalid, M.M.; Taha, T.Y.; Tabata, T.; Hayashi, J.M.; Soveg, F.W.; Carlson-Stevermer, J.; et al. Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2. Cell Rep. 2022, 40, 111088. [Google Scholar] [CrossRef]
- Pooladanda, V.; Thatikonda, S.; Muvvala, S.P.; Devabattula, G.; Godugu, C. BRD4 targeting nanotherapy prevents lipopolysaccharide induced acute respiratory distress syndrome. Int. J. Pharm. 2021, 601, 120536. [Google Scholar] [CrossRef]
- Pooladanda, V.; Thatikonda, S.; Priya Muvvala, S.; Godugu, C. Acute respiratory distress syndrome enhances tumor metastasis into lungs: Role of BRD4 in the tumor microenvironment. Int. Immunopharmacol. 2023, 115, 109701. [Google Scholar] [CrossRef]
- Xiao, X.; Fan, Y.; Li, J.; Zhang, X.; Lou, X.; Dou, Y.; Shi, X.; Lan, P.; Xiao, Y.; Minze, L.; et al. Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation. J. Exp. Med. 2018, 215, 559–574. [Google Scholar] [CrossRef]
- Perry, M.M.; Durham, A.L.; Austin, P.J.; Adcock, I.M.; Chung, K.F. BET bromodomains regulate transforming growth factor-beta-induced proliferation and cytokine release in asthmatic airway smooth muscle. J. Biol. Chem. 2015, 290, 9111–9121. [Google Scholar] [CrossRef] [PubMed]
- Clifford, R.L.; Patel, J.K.; John, A.E.; Tatler, A.L.; Mazengarb, L.; Brightling, C.E.; Knox, A.J. CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: Regulation by BET. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 308, L962–L972. [Google Scholar] [CrossRef] [PubMed]
- Tian, B.; Liu, Z.; Litvinov, J.; Maroto, R.; Jamaluddin, M.; Rytting, E.; Patrikeev, I.; Ochoa, L.; Vargas, G.; Motamedi, M.; et al. Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 Inhibitors in Innate Inflammation-Driven Airway Remodeling. Am. J. Respir. Cell Mol. Biol. 2019, 60, 68–83. [Google Scholar] [CrossRef] [PubMed]
- Lu, X.; Zhang, H.; Wang, M.; Qu, F.; Li, J.; Li, R.; Yan, X. Novel insights into the role of BRD4 in fine particulate matter induced airway hyperresponsiveness. Ecotoxicol. Environ. Saf. 2021, 221, 112440. [Google Scholar] [CrossRef] [PubMed]
- Tian, B.; Yang, J.; Zhao, Y.; Ivanciuc, T.; Sun, H.; Garofalo, R.P.; Brasier, A.R. BRD4 Couples NF-kappaB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection. J. Virol. 2017, 91, e00007-17. [Google Scholar] [CrossRef]
- Tian, B.; Hosoki, K.; Liu, Z.; Yang, J.; Zhao, Y.; Sun, H.; Zhou, J.; Rytting, E.; Kaphalia, L.; Calhoun, W.J.; et al. Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. J. Allergy Clin. Immunol. 2019, 143, 1380–1394.e9. [Google Scholar] [CrossRef]
- Meloche, J.; Potus, F.; Vaillancourt, M.; Bourgeois, A.; Johnson, I.; Deschamps, L.; Chabot, S.; Ruffenach, G.; Henry, S.; Breuils-Bonnet, S.; et al. Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension. Circ. Res. 2015, 117, 525–535. [Google Scholar] [CrossRef]
- Chabert, C.; Khochbin, S.; Rousseaux, S.; Veyrenc, S.; Furze, R.; Smithers, N.; Prinjha, R.K.; Schlattner, U.; Pison, C.; Dubouchaud, H. Inhibition of BET Proteins Reduces Right Ventricle Hypertrophy and Pulmonary Hypertension Resulting from Combined Hypoxia and Pulmonary Inflammation. Int. J. Mol. Sci. 2018, 19, 2224. [Google Scholar] [CrossRef]
- Van der Feen, D.E.; Kurakula, K.; Tremblay, E.; Boucherat, O.; Bossers, G.P.L.; Szulcek, R.; Bourgeois, A.; Lampron, M.C.; Habbout, K.; Martineau, S.; et al. Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 2019, 200, 910–920. [Google Scholar] [CrossRef]
- Mumby, S.; Gambaryan, N.; Meng, C.; Perros, F.; Humbert, M.; Wort, S.J.; Adcock, I.M. Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension. Respirology 2017, 22, 157–164. [Google Scholar] [CrossRef]
- Tang, X.; Peng, R.; Ren, Y.; Apparsundaram, S.; Deguzman, J.; Bauer, C.M.; Hoffman, A.F.; Hamilton, S.; Liang, Z.; Zeng, H.; et al. BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in bleomycin-induced pulmonary fibrosis. Mol. Pharmacol. 2013, 83, 283–293. [Google Scholar] [CrossRef]
- Tang, X.; Peng, R.; Phillips, J.E.; Deguzman, J.; Ren, Y.; Apparsundaram, S.; Luo, Q.; Bauer, C.M.; Fuentes, M.E.; DeMartino, J.A.; et al. Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis. Am. J. Pathol. 2013, 183, 470–479. [Google Scholar] [CrossRef]
- Bernau, K.; Skibba, M.; Leet, J.P.; Furey, S.; Gehl, C.; Li, Y.; Zhou, J.; Sandbo, N.; Brasier, A.R. Selective Inhibition of Bromodomain-Containing Protein 4 Reduces Myofibroblast Transdifferentiation and Pulmonary Fibrosis. Front. Mol. Med. 2022, 2, 842558. [Google Scholar] [CrossRef] [PubMed]
- Kaneshita, S.; Kida, T.; Yoshioka, M.; Nishioka, K.; Raje, M.; Sakashita, A.; Hirano, A.; Sagawa, T.; Kasahara, A.; Inoue, T.; et al. CG223, a novel BET inhibitor, exerts TGF-beta1-mediated antifibrotic effects in a murine model of bleomycin-induced pulmonary fibrosis. Pulm. Pharmacol. Ther. 2021, 70, 102057. [Google Scholar] [CrossRef] [PubMed]
- Stock, C.J.W.; Michaeloudes, C.; Leoni, P.; Durham, A.L.; Mumby, S.; Wells, A.U.; Chung, K.F.; Adcock, I.M.; Renzoni, E.A.; Lindahl, G.E. Bromodomain and Extraterminal (BET) Protein Inhibition Restores Redox Balance and Inhibits Myofibroblast Activation. Biomed. Res. Int. 2019, 2019, 1484736. [Google Scholar] [CrossRef] [PubMed]
- Sanders, Y.Y.; Lyv, X.; Zhou, Q.J.; Xiang, Z.; Stanford, D.; Bodduluri, S.; Rowe, S.M.; Thannickal, V.J. Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice. JCI Insight. 2020, 5, e137127. [Google Scholar] [CrossRef]
- Suzuki, K.; Kim, J.D.; Ugai, K.; Matsuda, S.; Mikami, H.; Yoshioka, K.; Ikari, J.; Hatano, M.; Fukamizu, A.; Tatsumi, K.; et al. Transcriptomic changes involved in the dedifferentiation of myofibroblasts derived from the lung of a patient with idiopathic pulmonary fibrosis. Mol. Med. Rep. 2020, 22, 1518–1526. [Google Scholar] [CrossRef]
- Wang, J.; Zhou, F.; Li, Z.; Mei, H.; Wang, Y.; Ma, H.; Shi, L.; Huang, A.; Zhang, T.; Lin, Z.; et al. Pharmacological targeting of BET proteins attenuates radiation-induced lung fibrosis. Sci. Rep. 2018, 8, 998. [Google Scholar] [CrossRef]
- Khan, Y.M.; Kirkham, P.; Barnes, P.J.; Adcock, I.M. Brd4 is essential for IL-1beta-induced inflammation in human airway epithelial cells. PLoS ONE 2014, 9, e95051. [Google Scholar] [CrossRef]
- Malhotra, R.; Kurian, N.; Zhou, X.H.; Jiang, F.; Monkley, S.; DeMicco, A.; Clausen, I.G.; Dellgren, G.; Edenro, G.; Ahdesmaki, M.J.; et al. Altered regulation and expression of genes by BET family of proteins in COPD patients. PLoS ONE 2017, 12, e0173115. [Google Scholar]
- Michaeloudes, C.; Mercado, N.; Clarke, C.; Bhavsar, P.K.; Adcock, I.M.; Barnes, P.J.; Chung, K.F. Bromodomain and extraterminal proteins suppress NF-E2-related factor 2-mediated antioxidant gene expression. J. Immunol. 2014, 192, 4913–4920. [Google Scholar] [CrossRef] [PubMed]
- Zakarya, R.; Chan, Y.L.; Rutting, S.; Reddy, K.; Bozier, J.; Woldhuis, R.R.; Xenaki, D.; Van Ly, D.; Chen, H.; Brandsma, C.A.; et al. BET proteins are associated with the induction of small airway fibrosis in COPD. Thorax 2021, 76, 647–655. [Google Scholar] [CrossRef]
- Liu, Y.; Huang, Z.Z.; Min, L.; Li, Z.F.; Chen, K. The BRD4 inhibitor JQ1 protects against chronic obstructive pulmonary disease in mice by suppressing NF-kappaB activation. Histol. Histopathol. 2021, 36, 101–112. [Google Scholar] [PubMed]
- Duan, Y.; Zhou, S.; Wang, J. BRD4 is involved in viral exacerbation of chronic obstructive pulmonary disease. Respir. Res. 2023, 24, 37. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Zuo, Y.; Gao, Z. CircANKRD11 Knockdown Protects HPMECs from Cigarette Smoke Extract-Induced Injury by Regulating miR-145-5p/BRD4 Axis. Int. J. Chron. Obstruct. Pulmon. Dis. 2021, 16, 887–899. [Google Scholar] [CrossRef]
- Zheng, C.; Zhang, Y.; Zhao, Y.; Duan, Y.; Mu, Q.; Wang, X. Circ-OSBPL2 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-193a-5p/BRD4 Axis. Int. J. Chron. Obstruct. Pulmon. Dis. 2021, 16, 919–931. [Google Scholar] [CrossRef]
- Liu, X.; Wang, J.; Luo, H.; Xu, C.; Chen, X.; Zhang, R. MiR-218 Inhibits CSE-Induced Apoptosis and Inflammation in BEAS-2B by Targeting BRD4. Int. J. Chron. Obstruct. Pulmon. Dis. 2020, 15, 3407–3416. [Google Scholar] [CrossRef]
- Tang, K.; Zhao, J.; Xie, J.; Wang, J. Decreased miR-29b expression is associated with airway inflammation in chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell Mol. Physiol. 2019, 316, L621–L629. [Google Scholar] [CrossRef]
- Song, J.; Wang, Q.; Zong, L. LncRNA MIR155HG contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-128-5p/BRD4 axis. Biosci. Rep. 2020, 40, BSR20192567. [Google Scholar] [CrossRef]
- Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; et al. Selective inhibition of BET bromodomains. Nature 2010, 468, 1067–1073. [Google Scholar] [CrossRef]
- Nicodeme, E.; Jeffrey, K.L.; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C.W.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010, 468, 1119–1123. [Google Scholar] [CrossRef]
- Hu, B.; Guo, H.; Zhou, P.; Shi, Z.L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 2021, 19, 141–154. [Google Scholar] [CrossRef] [PubMed]
- Vann, K.R.; Acharya, A.; Jang, S.M.; Lachance, C.; Zandian, M.; Holt, T.A.; Smith, A.L.; Pandey, K.; Durden, D.L.; El-Gamal, D.; et al. Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection. Structure 2022, 30, 1224–1232.e5. [Google Scholar] [CrossRef] [PubMed]
- Mills, R.J.; Humphrey, S.J.; Fortuna, P.R.J.; Lor, M.; Foster, S.R.; Quaife-Ryan, G.A.; Johnston, R.L.; Dumenil, T.; Bishop, C.; Rudraraju, R.; et al. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection. Cell 2021, 184, 2167–2182.e22. [Google Scholar] [CrossRef] [PubMed]
- Matthay, M.A.; Zemans, R.L.; Zimmerman, G.A.; Arabi, Y.M.; Beitler, J.R.; Mercat, A.; Herridge, M.; Randolph, A.G.; Calfee, C.S. Acute respiratory distress syndrome. Nat. Rev. Dis. Primers 2019, 5, 18. [Google Scholar] [CrossRef]
- Wu, C.; Chen, X.; Cai, Y.; Xia, J.; Zhou, X.; Xu, S.; Huang, H.; Zhang, L.; Zhou, X.; Du, C.; et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. 2020, 180, 934–943. [Google Scholar] [CrossRef]
- Bosnjak, B.; Stelzmueller, B.; Erb, K.J.; Epstein, M.M. Treatment of allergic asthma: Modulation of Th2 cells and their responses. Respir. Res. 2011, 12, 114. [Google Scholar] [CrossRef]
- Zhao, L.; Wang, Y.; Jaganathan, A.; Sun, Y.; Ma, N.; Li, N.; Han, X.; Sun, X.; Yi, H.; Fu, S.; et al. BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation. EMBO J. 2023, 42, e111473. [Google Scholar] [CrossRef]
- Kawaguchi, M.; Onuchic, L.F.; Li, X.D.; Essayan, D.M.; Schroeder, J.; Xiao, H.Q.; Liu, M.C.; Krishnaswamy, G.; Germino, G.; Huang, S.K. Identification of a novel cytokine, ML-1, and its expression in subjects with asthma. J. Immunol. 2001, 167, 4430–4435. [Google Scholar] [CrossRef]
- Nakajima, M.; Kawaguchi, M.; Matsuyama, M.; Ota, K.; Fujita, J.; Matsukura, S.; Huang, S.K.; Morishima, Y.; Ishii, Y.; Satoh, H.; et al. Transcription Elongation Factor P-TEFb Is Involved in IL-17F Signaling in Airway Smooth Muscle Cells. Int. Arch. Allergy Immunol. 2018, 176, 83–90. [Google Scholar] [CrossRef]
- Johnson, S.R.; Knox, A.J. Synthetic functions of airway smooth muscle in asthma. Trends Pharmacol. Sci. 1997, 18, 288–292. [Google Scholar] [CrossRef] [PubMed]
- McKay, S.; Sharma, H.S. Autocrine regulation of asthmatic airway inflammation: Role of airway smooth muscle. Respir. Res. 2002, 3, 11. [Google Scholar] [CrossRef] [PubMed]
- Lazaar, A.L.; Panettieri, R.A., Jr. Airway smooth muscle: A modulator of airway remodeling in asthma. J. Allergy Clin. Immunol. 2005, 116, 488–495, quiz 496. [Google Scholar] [CrossRef]
- Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146, 904–917. [Google Scholar] [CrossRef] [PubMed]
- Muhar, M.; Ebert, A.; Neumann, T.; Umkehrer, C.; Jude, J.; Wieshofer, C.; Rescheneder, P.; Lipp, J.J.; Herzog, V.A.; Reichholf, B.; et al. SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis. Science 2018, 360, 800–805. [Google Scholar] [CrossRef]
- Qian, G.Q.; Yao, W.L.; Zhang, S.; Bajpai, R.; Hall, W.D.; Shanmugam, M.; Lonial, S.; Sun, S.Y. Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy. Cancer Lett. 2018, 435, 44–54. [Google Scholar] [CrossRef]
- Liu, R.; Bai, J.; Xu, G.; Xuan, L.; Zhang, T.; Meng, A.; Hou, Q. Multi-allergen challenge stimulates steriod-resistant airway inflammation via NF-kappaB-mediated IL-8 expression. Inflammation 2013, 36, 845–854. [Google Scholar] [CrossRef]
- John, A.E.; Zhu, Y.M.; Brightling, C.E.; Pang, L.; Knox, A.J. Human airway smooth muscle cells from asthmatic individuals have CXCL8 hypersecretion due to increased NF-kappa B p65, C/EBP beta, and RNA polymerase II binding to the CXCL8 promoter. J. Immunol. 2009, 183, 4682–4692. [Google Scholar] [CrossRef]
- Albarnaz, J.D.; Ren, H.; Torres, A.A.; Shmeleva, E.V.; Melo, C.A.; Bannister, A.J.; Brember, M.P.; Chung, B.Y.; Smith, G.L. Molecular mimicry of NF-kappaB by vaccinia virus protein enables selective inhibition of antiviral responses. Nat. Microbiol. 2022, 7, 154–168. [Google Scholar] [CrossRef]
- Brasier, A.R.; Zhou, J. Validation of the epigenetic reader bromodomain-containing protein 4 (BRD4) as a therapeutic target for treatment of airway remodeling. Drug Discov. Today 2020, 25, 126–132. [Google Scholar] [CrossRef]
- Devaiah, B.N.; Case-Borden, C.; Gegonne, A.; Hsu, C.H.; Chen, Q.; Meerzaman, D.; Dey, A.; Ozato, K.; Singer, D.S. BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin. Nat. Struct. Mol. Biol. 2016, 23, 540–548. [Google Scholar] [CrossRef] [PubMed]
- Courboulin, A.; Paulin, R.; Giguere, N.J.; Saksouk, N.; Perreault, T.; Meloche, J.; Paquet, E.R.; Biardel, S.; Provencher, S.; Cote, J.; et al. Role for miR-204 in human pulmonary arterial hypertension. J. Exp. Med. 2011, 208, 535–548. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Zhang, Y.; Zhou, D.; Cao, G.; Wu, Y. miR-204 enhances p27 mRNA stability by targeting Brd4 in head and neck squamous cell carcinoma. Oncol. Lett. 2018, 16, 4179–4184. [Google Scholar] [CrossRef] [PubMed]
- Provencher, S.; Potus, F.; Blais-Lecours, P.; Bernard, S.; Martineau, S.; Breuils-Bonnet, S.; Weatherald, J.; Sweeney, M.; Kulikowski, E.; Boucherat, O.; et al. BET Protein Inhibition for Pulmonary Arterial Hypertension: A Pilot Clinical Trial. Am. J. Respir. Crit. Care Med. 2022, 205, 1357–1360. [Google Scholar] [CrossRef]
- Liu, Y.; Wang, X.; Zhang, J.; Huang, H.; Ding, B.; Wu, J.; Shi, Y. Structural basis and binding properties of the second bromodomain of Brd4 with acetylated histone tails. Biochemistry 2008, 47, 6403–6417. [Google Scholar] [CrossRef] [PubMed]
- Murphy-Ullrich, J.E.; Suto, M.J. Thrombospondin-1 regulation of latent TGF-beta activation: A therapeutic target for fibrotic disease. Matrix Biol. 2018, 68–69, 28–43. [Google Scholar] [CrossRef]
- Nishimura, S.L. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am. J. Pathol. 2009, 175, 1362–1370. [Google Scholar] [CrossRef]
- Asano, Y.; Ihn, H.; Yamane, K.; Jinnin, M.; Mimura, Y.; Tamaki, K. Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J. Immunol. 2005, 175, 7708–7718. [Google Scholar] [CrossRef]
- Teixeira, K.C.; Soares, F.S.; Rocha, L.G.; Silveira, P.C.; Silva, L.A.; Valenca, S.S.; Dal Pizzol, F.; Streck, E.L.; Pinho, R.A. Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulm. Pharmacol. Ther. 2008, 21, 309–316. [Google Scholar] [CrossRef]
- Manoury, B.; Nenan, S.; Leclerc, O.; Guenon, I.; Boichot, E.; Planquois, J.M.; Bertrand, C.P.; Lagente, V. The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir. Res. 2005, 6, 11. [Google Scholar] [CrossRef]
- Cella, L.; Liuzzi, R.; D’Avino, V.; Conson, M.; Di Biase, A.; Picardi, M.; Pugliese, N.; Solla, R.; Salvatore, M.; Pacelli, R. Pulmonary damage in Hodgkin’s lymphoma patients treated with sequential chemo-radiotherapy: Predictors of radiation-induced lung injury. Acta Oncol. 2014, 53, 613–619. [Google Scholar] [CrossRef] [PubMed]
- Jin, H.; Yoo, Y.; Kim, Y.; Kim, Y.; Cho, J.; Lee, Y.S. Radiation-Induced Lung Fibrosis: Preclinical Animal Models and Therapeutic Strategies. Cancers 2020, 12, 1561. [Google Scholar] [CrossRef] [PubMed]
- Diseases, G.B.D.; Injuries, C. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020, 396, 1204–1222. [Google Scholar]
- Bhagwat, A.S.; Roe, J.S.; Mok, B.Y.L.; Hohmann, A.F.; Shi, J.; Vakoc, C.R. BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements. Cell Rep. 2016, 15, 519–530. [Google Scholar] [CrossRef] [PubMed]
- Devaiah, B.N.; Lewis, B.A.; Cherman, N.; Hewitt, M.C.; Albrecht, B.K.; Robey, P.G.; Ozato, K.; Sims, R.J., 3rd; Singer, D.S. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc. Natl. Acad. Sci. USA 2012, 109, 6927–6932. [Google Scholar] [CrossRef] [PubMed]
BET Protein | BET Inhibition | Cell Type | Treatment | Target Gene | Signal Pathway | In Vivo Model | Ref. |
---|---|---|---|---|---|---|---|
Acute lung inflammation | |||||||
BRD4 | ZL0454 | A549, human small airway epithelial cell | RSV | JUN, FOSL1 | AP-1 | N/A | [11] |
N/A | CPI-203 | Human bronchial epithelial cell | N/A | Th17 cytokines (e.g., IL17A, IL22) | N/A | Pseudomonas aeruginosa infection mouse model | [21] |
BRD2, BRD4 | JQ1, shRNA | Human umbilical vein endothelial cell; leukocyte | TNF-α | IL6, IL8 | NF-κB, p38, JNK MAPK | LPS mouse model | [22] |
N/A | IBET762, JQ1, RVX-297 | Human U937, PBMC, and fibroblast; mouse B cell and BMDM | LPS | IL6, IL17A | N/A | Rat and mouse collagen-induced arthritis model; mouse collagen antibody-induced arthritis model; LPS mouse model | [23] |
BRD4 | ZL0420, ZL0454, JQ1, RVX-208 | Human small airway epithelial cell | Poly(I:C) | ISG54, ISG56, IL8, CXCL2 | N/A | Poly(I:C) mouse model | [24] |
BRD2, BRD4 | N/A | HEK-293T/17 | SARS-CoV-2 | N/A | N/A | N/A | [25] |
N/A | JQ1, OTX015, ZBC260 | Murine lung bronchial and nonbronchial cells, LNCaP, H1437 | SARS-CoV-2 | ACE2, TMPRSS2 | N/A | N/A | [26] |
BRD2, BRD3, BRD4 | JQ1, dBET6, ABBV-744 | HEK293T, A549, Calu3 | SARS-CoV-2 | IFNB1, ISG15, IL6 | N/A | K18-hACE2 mouse model | [27] |
BRD4 upregulation | BRD4 siRNA | RAW 264.7 and BEAS-2B | LPS | IL-1β, IL6, IL17A, IL22 | NF-κB, STAT3, Akt/mTOR/MAPK | LPS-induced mouse model; xenograft mouse model | [28,29] |
Asthma | |||||||
BRD4 | JQ1, BRD4 siRNA | Th9 cell | OX40 | IL9 | NF-κB | Acute allergic lung inflammation mouse model; adopt transfer mouse model | [30] |
BRD4 | JQ1, I-BET762, BRD4 siRNA | Human airway smooth muscle cell | FCS + TGF-β | IL6, IL8 | N/A | N/A | [31] |
BRD3, BRD4 | JQ1, PFI-1, I-BET | Human airway smooth muscle cell | N/A | IL8 | RNA Pol II binding | N/A | [32] |
BRD4 | ZL0420, ZL0454, JQ1, RVX208 | Human small airway epithelial cell; human lung fibroblast | Poly(I:C) | N/A | N/A | Poly(I:C) mouse model | [33] |
BRD4 upregulation | ZL0420, BRD4 siRNA | Human airway smooth muscle cell | PM2.5 | MMP2, MMP9 | N/A | PM2.5 challenged mouse model | [34] |
BRD4 | JQ1, BRD4 siRNA | Human small airway epithelial cell | RSV | IRF1, IRF7, RIGI, Il6, Cxcl1, Cxcl2 | NF-κB | Poly(I:C) mouse model; RSV infection mouse model | [35] |
BRD4 | ZL0454 | Human small airway epithelial cell | Cat dander | SNAI1, CDH1, Acta2, Fn1, Cxcl1, Il6, Vim, Col1a1 | NF-κB | Cat dander exposed mouse model | [36] |
PAH | |||||||
BRD4 upregulation | JQ1, BRD4 siRNA | Pulmonary artery smooth muscle cells | N/A | CDKN1A, NFAT, BCL2, BIRC5 | N/A | Sugen/hypoxia rat model | [37] |
N/A | I-BET151 | N/A | N/A | N/A | N/A | LPS plus hypoxia rat model | [38] |
BRD4 upregulation | RVX-208, BRD4 siRNA | Human pulmonary microvascular endothelial cell, human pulmonary microvascular smooth muscle cell | TNF-α | FoxM1, PLK1 | N/A | Sugen5416 + hypoxia rat PAH model; monocrotaline + shunt PAH model; Pulmonary artery banding rat model | [39] |
N/A | JQ1 | Human pulmonary microvascular endothelial cell | FCS | IL6, IL8, CDKN1A | NF-κB | N/A | [40] |
Pulmonary fibrosis | |||||||
BRD4 | JQ1, I-BET | Human lung fibroblast | TGF-β, PDGF-BB | ACTA2, IL6, PAI1 | N/A | Bleomycin challenged mouse model | [41] |
BRD4 | JQ1 | Human lung fibroblast | TGF-β, PDGF-BB | IL6, IL8, CDKN1A | N/A | Bleomycin challenged mouse model | [42] |
BRD4 | ZL0591 | N/A | N/A | N/A | N/A | Bleomycin challenged mouse model | [43] |
BRD4 upregulation | CG223 | mouse lung fibroblast | TGF-β | Thbs1, Itgb3, Acta2 | N/A | Bleomycin challenged mouse model | [44] |
BRD2, BRD3, BRD4 | JQ1 | Human lung fibroblast | TGF-β | NOX4, SOD2 | N/A | N/A | [45] |
BRD4 | JQ1, I-BET762, OTX015 | Human lung fibroblast | TGF-β | NOX4 | N/A | Aged mice challenged with bleomycin | [46] |
N/A | JQ1 | Human lung fibroblast and myofibroblast | TGF-β | ACTA1, FN1 | N/A | N/A | [47] |
BRD4 upregulation | JQ1 | Human lung fibroblast | Radiation | MYC, TGFB1 | Smad2/3, NF-κB | Radiation-induced pulmonary fibrosis | [48] |
COPD | |||||||
BRD2, BRD4 | JQ1, PFI-1 | Human bronchial epithelial cell | H2O2, IL-1β | IL6, IL8 | NF-κB | N/A | [49] |
N/A | JQ1 | Human alveolar macrophages, peripheral blood mononuclear cells (PBMC) | LPS | Cell- and time-dependent genes, not listed here | N/A | N/A | [50] |
BRD2, BRD3, BRD4 | JQ1 | Human airway smooth muscle cell, THP-1 cell, PMBC | CSE | HO1, NQO1, GCLC | Nrf2 | N/A | [51] |
N/A | JQ1 | Human airway smooth muscle cell | TGF-β | COL15A1, TNC | N/A | N/A | [52] |
N/A | JQ1 | N/A | N/A | Mmp2, Mmp9, Ifng, Il17, Il1b, Il6, Tnf, Il10 | NF-κB | CSE plus LPS induced mouse model | [53] |
BRD4 upregulation | JQ1 | BEAS-2B | CSE plus flu | IL6, IL8, CXCL1 | N/A | CSE plus flu infection mouse model | [54] |
BRD4 upregulation | N/A | Human pulmonary microvascular endothelial cell | CSE | BCL2, BAX, TNF, IL1B, IL6 | CircANKRD11/miR-145-5p/BRD4 | N/A | [55] |
BRD4 upregulation | N/A | Human bronchial epithelial cell (16HBE) | CSE | IL8, IL1B, TNF | Circ-OSBPL2/miR-193a-5p/BRD4 | N/A | [56] |
BRD4 upregulation | BRD4 siRNA | BEAS-2B | CSE | IL8, IL1B, TNF | miR-218/BRD4 | N/A | [57] |
BRD4 upregulation | BRD4 siRNA | Human bronchial epithelial cell (HBE4-E6/E7) | CSE | IL6, IL8 | miR-29b/BRD4 | N/A | [58] |
BRD4 | N/A | Human pulmonary microvascular endothelial cell | CSE | BCL2, BAX, IL6, IL8, TNF | MIR155HG/miR-218-5p/BRD4 | N/A | [59] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Guo, X.; Olajuyin, A.; Tucker, T.A.; Idell, S.; Qian, G. BRD4 as a Therapeutic Target in Pulmonary Diseases. Int. J. Mol. Sci. 2023, 24, 13231. https://doi.org/10.3390/ijms241713231
Guo X, Olajuyin A, Tucker TA, Idell S, Qian G. BRD4 as a Therapeutic Target in Pulmonary Diseases. International Journal of Molecular Sciences. 2023; 24(17):13231. https://doi.org/10.3390/ijms241713231
Chicago/Turabian StyleGuo, Xia, Ayobami Olajuyin, Torry A. Tucker, Steven Idell, and Guoqing Qian. 2023. "BRD4 as a Therapeutic Target in Pulmonary Diseases" International Journal of Molecular Sciences 24, no. 17: 13231. https://doi.org/10.3390/ijms241713231