Bromodomain Inhibitor JQ1 as a Candidate Therapeutic Agent in Malignant Pleural Mesothelioma

  • Cinaria T. Albadri St. James’s Hospital, Trinity Centre for Health Sciences, Trinity College Dublin University, Ireland
Keywords: Bromodomain and extraterminal domain, JQ1, Malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare tumor that develops from the mesothelial linings of the pleural, pericardial, and peritoneal cavities. The actual risk factor for developing the disease is exposure to asbestos in workplace. Bromodomain and extraterminal (BET) domain proteins are epigenetic signaling agents that associate with acetylated histones and expedite the transcription of target genes. This study investigates whether the small molecule BET protein inhibitor JQ1 specifically may be an effective therapy for MPM. Reverse transcriptase polymerase chain reaction methods reveal an inclusive change in gene expression implying that JQ1 is a potential inhibitor which targets the BET proteins. Our results report that JQ1 has tumor-suppressive effects as it significantly ceased cellular activity in MPM cell lines. We predict that JQ1 may be the promising therapy for pleural mesothelioma cancers.

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References

B. Kroczynska, R. Cutrone, M. Bocchetta, H. Yang, A. G. Elmishad, P. Vacek, M. Ramos-Nino, B. T. Mossman, H. I. Pass and M. Carbone. Crocidolite asbestos and SV40 are co-carcinogens in human mesothelial cells and in causing mesothelioma in hamsters”. Proc Natl Acad Sci USA vol. 103, pp. 14128-14133, 2006.

B. W. S. Robinson, A. W. Musk and A. Lake. “Malignant mesothelioma”. Lancet, vol. 366, pp. 397-408, 2005.

M. Carbone, B. H. Ly, R. F. Dodson, I. Pagano, P. T. Morris, U. A. Dogan, A. F. Gazdar, H. I. Pass and H. Yang. “Malignant mesothelioma: Facts, myths, and hypotheses”. Journal of Cellular Physiology, vol. 227, pp. 44-58, 2012.

S. Y. Wu, A. Y. Lee, H. T. Lai, H. Zhang and C. M. Chiang. “Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting”. Molecular Cell, vol. 49, pp. 843-857, 2013.

P. Filippakopoulos, S. Picaud, M. Mangos, T. Keates, J. Lambert, D. Barsyte-Lovejoy, I. Felletar, R. Volkmer, S. Muller, T. Pawson, A. Gingras, C. Arrowsmith and S. Knapp. “Histone recognition and large-scale structural analysis of the human bromodomain family”. Cell, vol. 149, pp. 214-231, 2012.

P. Filippakopoulos, J. Qi, S. Picaud, Y. Shen, W. B. Smith, O. Fedorov, E. M. Morse, T. Keates, T. T. Hickman, I. Felletar, M. Philpott, S. Munro, M. R. McKeown, Y. Wang, A. L. Christie, N. West, M. J. Cameron, B. Schwartz, T. D. Heightman, N. La Thangue, C. A. French, O. West, A. L. Kung, S. Knapp and J. E. Bradner. “Selective inhibition of BET bromodomains”. Nature, vol. 468, pp. 1067-1073, 2010.

M. A. Dawson, R. K. Prinjha, A. Dittman, G. Giotopoulos, M. Bantscheff, W. I. Chan, S. C. Robson, C. Chung, C. Hopf, M. M. Savitski, C. Huthmacher, E. Gudgin, D. Lugo, S. Beinke, T. D. Chapman, E. J. Roberts, P. E. Soden, K. R. Auger, O. Mirguet, K. Doehner, R. Delwel, A. K. Burnett, P. Jeffrey, G. Drewes, K. Lee, B. J. Huntly and T. Kouzarides T. “Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia”. Nature, vol. 478, pp. 529-533, 2011.

J. E. Delmore, G. C. Issa, M. E. Lemieux, P. B. Rahl, J. Shi, H. M. Jacobs, E. Kastritis, T. Gilpatrick, R. M. Paranal, J. Qi, M. Chesi, A. Schinzel, M. R. McKeown, T. P. Heffernan, C. R. Vakoc, L. Bergsagel, I. M. Ghobrial, P. G. Richardson, R. A. Young, W. C. Hahn, K. C. Anderson, A. L. Kung, J. E. Bradner and C. S. Mitsiades. “BET bromodomain inhibition as a therapeutic strategy to target c-Myc”. Cell, vol. 146, pp. 904-917, 2011.

J. A. Mertz, A. R. Conery, B. M. Bryant, P. Sandy, S. Balasubramanian, D. A. Mele, L. Bergeron and R. J. Sims. “Targeting MYC dependence in cancer by inhibiting BET bromodomains”. Proc Natl Acad Sci USA, vol. 108, pp. 16669-16674, 2011.

B. C. Christensen, E. A. Houseman, J. J. Godleski, C. J. Marsit, J. L. Longaker, C. R. Roelofs, M. R. Karagas, M. R. Wrensch, R. Yeh, H. H. Nelson, J. L. Wiemels, S. Zheng, J. K. Wiencke, R. Bueno, D. J. Sugarbaker and K. T. Kelsey. “Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome”. Cancer Res, vol. 69, pp. 227-234, 2009.

P. K. Paik and L. M. Krug. “Histone deacetylase inhibitors in malignant pleural mesothelioma preclinical rationale and clinical trials”. J Thorac Oncol, vol. 5, pp. 275-279, 2010.

M. Yun, J. Wu, J. L. Workman and B. Li. “Readers of histone modifications”. Cell Res, vol. 21, pp. 564-578, 2011.

N. Sachini. “The Role of Lysine Acetylation, Histone Acetyltransferases and Bromodomain Containing Proteins in Cancer Development”. Master Thesis, UMC Utrecht, 2013.

V. Janson. “Cisplatin-resistance and Cell Death in Malignant Pleural Mesothelioma Cells”. Doctoral Thesis, Umeå University, 2008.

S. Picaud, D. D. Costa, A. Thanasopoulou, P. Filippakopoulos, P. V. Fish, M. Philpott, O. Fedorov, P. Brennan, M. E. Bunnage, D. R. Owen, J. E. Bradner, P. Taniere, B. O’Sullivan, S. Muller, J. Schwaller, T. Stankovic and S. Knapp. “PFI-1, a highly selective protein interaction inhibitor, targeting BET bromodomains”. Cancer Res, vol. 73, pp. 3336-3346, 2013.

Published
2020-01-17
How to Cite
1.
Albadri C. Bromodomain Inhibitor JQ1 as a Candidate Therapeutic Agent in Malignant Pleural Mesothelioma. cuesj [Internet]. 17Jan.2020 [cited 28Mar.2024];4(1):70-6. Available from: https://journals.cihanuniversity.edu.iq/index.php/cuesj/article/view/188
Section
Research Article