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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Overexpression of Bromodomain and Extraterminal Domain is Associated with Progression, Metastasis and Unfavorable Outcomes: Highlighting Prognostic and Therapeutic Value of the BET Protein Family in Gastric Cancer

Author(s): Shahrzad S. Fard, Shaghayegh Kouchaki, Zahra Salimian, Masoud Sotoudeh, Seyed A. Mousavi, Kamran Alimoghaddam and Seyed H. Ghaffari*

Volume 23, Issue 7, 2023

Published on: 15 November, 2022

Page: [794 - 806] Pages: 13

DOI: 10.2174/1871520623666221025145320

Price: $65

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Abstract

Background: As epigenetic readers, Bromodomain and extraterminal domain (BET) proteins have attracted immense interest in developing novel therapies targeting this family to inhibit cancer progression. Although the impact of BRD4 in the carcinogenesis of various tumors has been widely investigated, little is known about the potential roles of the BET family in gastric cancer.

Methods: In this cohort study, we have screened the expression profile of the BET protein family, including three members, BRD2, BRD3 and BRD4, in fresh gastric cancer (GC), adjacent non-tumor and normal gastric tissues, as well as the anti-cancer effects and molecular mechanisms of BET inhibition in GC cell lines.

Results: Among GC patients, BRD2, BRD3 and BRD4 showed overexpression, 48.07% (25/52), 61.5% (32/52) and 63.46% (33/52), respectively. The overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcomes (HR = 2.023, P = 0.038; HR = 3.874, P = 0.001, respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression could not be used as an independent prognostic factor for GC patients after adjustment with other variables. I-BET151, a potent pan-inhibitor, suppressing the BET family, decreased cell growth, migration and invasion of GC cells. Interestingly, I-BET151 induced G1 cell cycle arrest through down-regulation of c-Myc and its target, CDK2/Cyclin D1 complex.

Conclusions: Our data provide insights into the prognostic role of the BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

Keywords: Bromodomain extraterminal domain family, gastric cancer, prognosis, targeted therapy, I-BET151, lymphoblastic leukemia.

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[1]
Hu, B.; El Hajj, N.; Sittler, S.; Lammert, N.; Barnes, R.; Meloni-Ehrig, A. Gastric cancer: Classification, histology and application of molecular pathology. J. Gastrointest. Oncol., 2012, 3(3), 251-261.
[PMID: 22943016]
[2]
Gadde, R.; Tamariz, L.; Hanna, M.; Avisar, E.; Livingstone, A.; Franceschi, D.; Yakoub, D. Metastatic gastric cancer (MGC) patients: Can we improve survival by metastasectomy? A systematic review and meta-analysis. J. Surg. Oncol., 2015, 112(1), 38-45.
[http://dx.doi.org/10.1002/jso.23945] [PMID: 26074130]
[3]
Panani, A.D. Cytogenetic and molecular aspects of gastric cancer: Clinical implications. Cancer Lett., 2008, 266(2), 99-115.
[http://dx.doi.org/10.1016/j.canlet.2008.02.053] [PMID: 18381231]
[4]
Kang, C.; Song, J.J.; Lee, J.; Kim, M.Y. Epigenetics: An emerging player in gastric cancer. World J. Gastroenterol., 2014, 20(21), 6433-6447.
[http://dx.doi.org/10.3748/wjg.v20.i21.6433] [PMID: 24914365]
[5]
Calcagno, D.Q.; Gigek, C.O.; Chen, E.S.; Burbano, R.R.; Smith, M.A. DNA and histone methylation in gastric carcinogenesis. World J. Gastroenterol., 2013, 19(8), 1182-1192.
[http://dx.doi.org/10.3748/wjg.v19.i8.1182] [PMID: 23482412]
[6]
Zhao, Y.; Yang, C.Y.; Wang, S. The making of I-BET762, a BET bromodomain inhibitor now in clinical development. J. Med. Chem., 2013, 56(19), 7498-7500.
[http://dx.doi.org/10.1021/jm4014407] [PMID: 24107192]
[7]
Puissant, A.; Frumm, S.M.; Alexe, G.; Bassil, C.F.; Qi, J.; Chanthery, Y.H.; Nekritz, E.A.; Zeid, R.; Gustafson, W.C.; Greninger, P.; Garnett, M.J.; McDermott, U.; Benes, C.H.; Kung, A.L.; Weiss, W.A.; Bradner, J.E.; Stegmaier, K. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov., 2013, 3(3), 308-323.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0418] [PMID: 23430699]
[8]
Montenegro, R.C.; Clark, P.G.K.; Howarth, A.; Wan, X.; Ceroni, A.; Siejka, P.; Nunez-Alonso, G.A.; Monteiro, O.; Rogers, C.; Gamble, V.; Burbano, R.; Brennan, P.E.; Tallant, C.; Ebner, D.; Fedorov, O.; O’Neill, E.; Knapp, S.; Dixon, D.; Müller, S. BET inhibition as a new strategy for the treatment of gastric cancer. Oncotarget, 2016, 7(28), 43997-44012.
[http://dx.doi.org/10.18632/oncotarget.9766] [PMID: 27259267]
[9]
Padmanabhan, B.; Mathur, S.; Manjula, R.; Tripathi, S. Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases. J. Biosci., 2016, 41(2), 295-311.
[http://dx.doi.org/10.1007/s12038-016-9600-6] [PMID: 27240990]
[10]
Sahai, V.; Redig, A.J.; Collier, K.A.; Eckerdt, F.D.; Munshi, H.G. Targeting BET bromodomain proteins in solid tumors. Oncotarget, 2016, 7(33), 53997-54009.
[http://dx.doi.org/10.18632/oncotarget.9804] [PMID: 27283767]
[11]
Devaiah, B.N.; Singer, D.S. Two faces of BRD4. Transcription, 2013, 4(1), 13-17.
[http://dx.doi.org/10.4161/trns.22542] [PMID: 23131666]
[12]
Momeny, M.; Eyvani, H.; Barghi, F.; Ghaffari, S.H.; Javadikooshesh, S.; Hassanvand Jamadi, R.; Esmaeili, F.; Alishahi, Z.; Zaghal, A.; Bashash, D.; Samani, F.S.; Ghaffari, P.; Dehpour, A.R.; Tavangar, S.M.; Alimoghaddam, K.; Ghavamzadeh, A. Inhibition of bromodomain and extraterminal domain reduces growth and invasive characteristics of chemoresistant ovarian carcinoma cells. Anticancer Drugs, 2018, 29(10), 1011-1020.
[http://dx.doi.org/10.1097/CAD.0000000000000681] [PMID: 30096128]
[13]
Chaidos, A.; Caputo, V.; Karadimitris, A. Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: Emerging preclinical and clinical evidence. Ther. Adv. Hematol., 2015, 6(3), 128-141.
[http://dx.doi.org/10.1177/2040620715576662] [PMID: 26137204]
[14]
Pérez-Salvia, M.; Esteller, M. Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics, 2017, 12(5), 323-339.
[http://dx.doi.org/10.1080/15592294.2016.1265710] [PMID: 27911230]
[15]
Tao, Z.; Li, X.; Wang, H.; Chen, G.; Feng, Z.; Wu, Y.; Yin, H.; Zhao, G.; Deng, Z.; Zhao, C.; Li, Y.; Sun, T.; Zhou, Y. BRD4 regulates self‐renewal ability and tumorigenicity of glioma‐initiating cells by enrichment in the Notch1 promoter region. Clin. Transl. Med., 2020, 10(6), e181.
[http://dx.doi.org/10.1002/ctm2.181] [PMID: 33135348]
[16]
Gao, Z.; Yuan, T.; Zhou, X.; Ni, P.; Sun, G.; Li, P.; Cheng, Z.; Wang, X. Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression. Cancer Biol. Ther., 2018, 19(5), 407-415.
[http://dx.doi.org/10.1080/15384047.2018.1423923] [PMID: 29333921]
[17]
Schmittgen, T.D.; Livak, K.J. Analyzing real-time PCR data by the comparative CT method. Nat. Protoc., 2008, 3(6), 1101-1108.
[http://dx.doi.org/10.1038/nprot.2008.73] [PMID: 18546601]
[18]
Soleymani Fard, S.; Yazdanbod, M.; Sotoudeh, M.; Bashash, D.; Mahmoodzadeh, H.; Saliminejad, K.; Mousavi, S.A.; Ghaffari, S.H.; Alimoghaddam, K. Prognostic and therapeutic significance of androgen receptor in patients with gastric cancer. OncoTargets Ther., 2020, 13, 9821-9837.
[http://dx.doi.org/10.2147/OTT.S265364] [PMID: 33061460]
[19]
Fard, S.S.; Saliminejad, K.; Sotoudeh, M.; Soleimanifard, N.; Kouchaki, S.; Yazdanbod, M.; Mahmoodzadeh, H.; Ghavamzadeh, A.; Malekzadeh, R.; Chahardouli, B.; Alimoghaddam, K.; Ghaffari, S.H. The correlation between EGFR and androgen receptor pathways: A novel potential prognostic marker in gastric cancer. Anticancer. Agents Med. Chem., 2020, 19(17), 2097-2107.
[http://dx.doi.org/10.2174/1871520619666190930142820] [PMID: 31566139]
[20]
Zhou, S.; Zhang, S.; Wang, L.; Huang, S.; Yuan, Y.; Yang, J.; Wang, H.; Li, X.; Wang, P.; Zhou, L.; Yang, J.; Xu, Y.; Gao, H.; Zhang, Y.; Lv, Y.; Zou, X. BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling. Oncogenesis, 2020, 9(3), 33.
[http://dx.doi.org/10.1038/s41389-020-0218-z] [PMID: 32157097]
[21]
Mazur, P.K.; Herner, A.; Mello, S.S.; Wirth, M.; Hausmann, S.; Sánchez-Rivera, F.J.; Lofgren, S.M.; Kuschma, T.; Hahn, S.A.; Vangala, D.; Trajkovic-Arsic, M.; Gupta, A.; Heid, I.; Noël, P.B.; Braren, R.; Erkan, M.; Kleeff, J.; Sipos, B.; Sayles, L.C.; Heikenwalder, M.; Heßmann, E.; Ellenrieder, V.; Esposito, I.; Jacks, T.; Bradner, J.E.; Khatri, P.; Sweet-Cordero, E.A.; Attardi, L.D.; Schmid, R.M.; Schneider, G.; Sage, J.; Siveke, J.T. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat. Med., 2015, 21(10), 1163-1171.
[http://dx.doi.org/10.1038/nm.3952] [PMID: 26390243]
[22]
Lenhart, R.; Kirov, S.; Desilva, H.; Cao, J.; Lei, M.; Johnston, K.; Peterson, R.; Schweizer, L.; Purandare, A.; Ross-Macdonald, P.; Fairchild, C.; Wong, T.; Wee, S. Sensitivity of small cell lung cancer to bet inhibition is mediated by regulation of ASCL1 gene expression. Mol. Cancer Ther., 2015, 14(10), 2167-2174.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0037] [PMID: 26253517]
[23]
Venkataraman, S.; Alimova, I.; Balakrishnan, I.; Harris, P.; Birks, D.K.; Griesinger, A.; Amani, V.; Cristiano, B.; Remke, M.; Taylor, M.D.; Handler, M.; Foreman, N.K.; Vibhakar, R. Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget, 2014, 5(9), 2355-2371.
[http://dx.doi.org/10.18632/oncotarget.1659] [PMID: 24796395]
[24]
Zou, Z.; Huang, B.; Wu, X.; Zhang, H.; Qi, J.; Bradner, J.; Nair, S.; Chen, L-F. Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene, 2014, 33(18), 2395-2404.
[http://dx.doi.org/10.1038/onc.2013.179] [PMID: 23686307]
[25]
Sinha, A.; Faller, D.V.; Denis, G.V. Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A. Biochem. J., 2005, 387(1), 257-269.
[http://dx.doi.org/10.1042/BJ20041793] [PMID: 15548137]
[26]
Yang, Z.; Yik, J.H.N.; 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(4), 535-545.
[http://dx.doi.org/10.1016/j.molcel.2005.06.029] [PMID: 16109377]
[27]
Feng, Q.; Zhang, Z.; Shea, M.J.; Creighton, C.J.; Coarfa, C.; Hilsenbeck, S.G.; Lanz, R.; He, B.; Wang, L.; Fu, X.; Nardone, A.; Song, Y.; Bradner, J.; Mitsiades, N.; Mitsiades, C.S.; Osborne, C.K.; Schiff, R.; O’Malley, B.W. An epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res., 2014, 24(7), 809-819.
[http://dx.doi.org/10.1038/cr.2014.71] [PMID: 24874954]
[28]
Zuber, J.; Shi, J.; Wang, E.; Rappaport, A.R.; Herrmann, H.; Sison, E.A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M.; Taylor, M.J.; Johns, C.; Chicas, A.; Mulloy, J.C.; Kogan, S.C.; Brown, P.; Valent, P.; Bradner, J.E.; Lowe, S.W.; Vakoc, C.R. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature, 2011, 478(7370), 524-528.
[http://dx.doi.org/10.1038/nature10334] [PMID: 21814200]
[29]
Lockwood, W.W.; Zejnullahu, K.; Bradner, J.E.; Varmus, H. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc. Natl. Acad. Sci. USA, 2012, 109(47), 19408-19413.
[http://dx.doi.org/10.1073/pnas.1216363109] [PMID: 23129625]
[30]
Sahai, V.; Kumar, K.; Knab, L.M.; Chow, C.R.; Raza, S.S.; Bentrem, D.J.; Ebine, K.; Munshi, H.G. BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen. Mol. Cancer Ther., 2014, 13(7), 1907-1917.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0925] [PMID: 24807963]
[31]
Song, H.; Shi, L.; Xu, Y.; Xu, T.; Fan, R.; Cao, M.; Xu, W.; Song, J. BRD4 promotes the stemness of gastric cancer cells via attenuating miR-216a-3p-mediated inhibition of Wnt/β-catenin signaling. Eur. J. Pharmacol., 2019, 852, 189-197.
[http://dx.doi.org/10.1016/j.ejphar.2019.03.018] [PMID: 30876979]
[32]
Ba, M.; Long, H.; Yan, Z.; Wang, S.; Wu, Y.; Tu, Y.; Gong, Y.; Cui, S. BRD4 promotes gastric cancer progression through the transcriptional and epigenetic regulation of c‐MYC. J. Cell. Biochem., 2018, 119(1), 973-982.
[http://dx.doi.org/10.1002/jcb.26264] [PMID: 28681984]
[33]
Braakhuis, B.J.M.; Leemans, C.R.; Brakenhoff, R.H. Using tissue adjacent to carcinoma as a normal control: An obvious but questionable practice. J. Pathol., 2004, 203(2), 620-621.
[http://dx.doi.org/10.1002/path.1549] [PMID: 15141375]
[34]
Hewings, D.S.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Picaud, S.; Tumber, A.; Wells, C.; Olcina, M.M.; Freeman, K.; Gill, A.; Ritchie, A.J.; Sheppard, D.W.; Russell, A.J.; Hammond, E.M.; Knapp, S.; Brennan, P.E.; Conway, S.J. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J. Med. Chem., 2013, 56(8), 3217-3227.
[http://dx.doi.org/10.1021/jm301588r] [PMID: 23517011]
[35]
Li, H.; Mo, J.; Jia, G.; Liu, C.; Luan, Z.; Guan, Y. Activation of Wnt signaling inhibits the pro-apoptotic role of Notch in gastric cancer cells. Mol. Med. Rep., 2013, 7(6), 1751-1756.
[http://dx.doi.org/10.3892/mmr.2013.1412] [PMID: 23563575]
[36]
Wyce, A.; Ganji, G.; Smitheman, K.N.; Chung, C.; Korenchuk, S.; Bai, Y.; Barbash, O.; Le, B.; Craggs, P.D.; McCabe, M.T.; Kennedy-Wilson, K.M.; Sanchez, L.V.; Gosmini, R.L.; Parr, N.; McHugh, C.F.; Dhanak, D.; Prinjha, R.K.; Auger, K.R.; Tummino, P.J. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS One, 2013, 8(8), e72967.
[http://dx.doi.org/10.1371/journal.pone.0072967] [PMID: 24009722]
[37]
Yang, Z.; He, N.; Zhou, Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol. Cell. Biol., 2008, 28(3), 967-976.
[http://dx.doi.org/10.1128/MCB.01020-07] [PMID: 18039861]
[38]
Li, G.Q.; Guo, W.Z.; Zhang, Y.; Seng, J.J.; Zhang, H.P.; Ma, X.X.; Zhang, G.; Li, J.; Yan, B.; Tang, H.W.; Li, S.S.; Wang, L.D.; Zhang, S.J. Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget, 2016, 7(3), 2462-2474.
[http://dx.doi.org/10.18632/oncotarget.6275] [PMID: 26575167]
[39]
Cheng, Z.; Gong, Y.; Ma, Y.; Lu, K.; Lu, X.; Pierce, L.A.; Thompson, R.C.; Muller, S.; Knapp, S.; Wang, J. Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin. Cancer Res., 2013, 19(7), 1748-1759.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3066] [PMID: 23403638]
[40]
Asangani, I.A.; Dommeti, V.L.; Wang, X.; Malik, R.; Cieslik, M.; Yang, R.; Escara-Wilke, J.; Wilder-Romans, K.; Dhanireddy, S.; Engelke, C.; Iyer, M.K.; Jing, X.; Wu, Y.M.; Cao, X.; Qin, Z.S.; Wang, S.; Feng, F.Y.; Chinnaiyan, A.M. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature, 2014, 510(7504), 278-282.
[http://dx.doi.org/10.1038/nature13229] [PMID: 24759320]
[41]
Hu, Y.; Zhou, J.; Ye, F.; Xiong, H.; Peng, L.; Zheng, Z.; Xu, F.; Cui, M.; Wei, C.; Wang, X.; Wang, Z.; Zhu, H.; Lee, P.; Zhou, M.; Jiang, B.; Zhang, D. BRD4 inhibitor inhibits colorectal cancer growth and metastasis. Int. J. Mol. Sci., 2015, 16(1), 1928-1948.
[http://dx.doi.org/10.3390/ijms16011928] [PMID: 25603177]
[42]
Wen, N.; Guo, B.; Zheng, H.; Xu, L.; Liang, H.; Wang, Q.; Wang, D.; Chen, X.; Zhang, S.; Li, Y.; Zhang, L. Bromodomain inhibitor jq1 induces cell cycle arrest and apoptosis of glioma stem cells through the VEGF/PI3K/AKT signaling pathway. Int. J. Oncol., 2019, 55(4), 879-895.
[http://dx.doi.org/10.3892/ijo.2019.4863] [PMID: 31485609]

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