@article{b914b26093f64a088e096334f51374b2,
title = "BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer",
abstract = "BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy. The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.",
keywords = "BRD2, BRD4, CRPC, DNA repair, NHEJ, TMPRSS2-ERG, gene fusion, genomic rearrangements, non-homologous end joining, prostate cancer",
author = "Xiangyi Li and Baek, {Guem Hee} and Ramanand, {Susmita G.} and Adam Sharp and Yunpeng Gao and Wei Yuan and Jon Welti and Rodrigues, {Daniel N.} and David Dolling and Ines Figueiredo and Semini Sumanasuriya and Mateus Crespo and Adam Aslam and Rui Li and Yi Yin and Bipasha Mukherjee and Mohammed Kanchwala and Hughes, {Ashley M.} and Halsey, {Wendy S.} and Chiang, {Cheng Ming} and Chao Xing and Raj, {Ganesh V.} and Sandeep Burma and {de Bono}, Johann and Mani, {Ram S.}",
note = "Funding Information: We thank M. Hardebeck and P. Todorova for technical assistance; B. Chen for the kind gift of Ku70 and Ku80 antibodies; A. Chinnaiyan, D. Castrillon, J. Malter, H. Sadek, and M.R.S. Rao for insightful comments and discussion; N. Safdar for manuscript edits. The authors acknowledge the assistance of the UT Southwestern Live Cell Imaging Facility, a Shared Resource of the Harold C. Simmons Cancer Center, is supported in part by an NCI Cancer Center Support Grant (1P30 CA142543-01). NIH Pathway to Independence (PI) Award (R00CA160640) to R.S.M. and startup funds from UT Southwestern supported research reported in this publication. R.S.M. also acknowledges funding from the ACS-IRG New Investigator Award in Cancer Research (IRG-02-196), and from the Prostate Cancer Research Program (PCRP) – Impact Award – US Department of Defense (W81XWH-17-1-0675). J.d.B. (W81XWH-17-1-0676) and G.V.R. (W81XWH-17-1-0674) acknowledges funding from the Prostate Cancer Research Program (PCRP) – Impact Award – US Department of Defense. The authors acknowledge funding from Prostate Cancer UK, the Prostate Cancer Foundation, Movember, Stand Up To Cancer, the US Department of Defense, Cancer Research UK, the UK Department of Health to the ICR/Royal Marsden ECMC, the Academy of Medical Sciences, and NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden and The Institute of Cancer Research. A.S. is supported by a Medical Research Council fellowship. S.B. is supported by grants from the NIH (RO1CA149461, RO1CA197796, and R21CA202403) and the National Aeronautics and Space Administration (NNX16AD78G). C.-M.C. is supported by grants from the NIH (CA103867), CPRIT (RP140367), and the Welch Foundation (I-1805). C.X. was partially supported by NIH grant UL1TR001105. Funding Information: We thank M. Hardebeck and P. Todorova for technical assistance; B. Chen for the kind gift of Ku70 and Ku80 antibodies; A. Chinnaiyan, D. Castrillon, J. Malter, H. Sadek, and M.R.S. Rao for insightful comments and discussion; N. Safdar for manuscript edits. The authors acknowledge the assistance of the UT Southwestern Live Cell Imaging Facility , a Shared Resource of the Harold C. Simmons Cancer Center , is supported in part by an NCI Cancer Center Support Grant ( 1P30 CA142543-01 ). NIH Pathway to Independence (PI) Award ( R00CA160640 ) to R.S.M. and startup funds from UT Southwestern supported research reported in this publication. R.S.M. also acknowledges funding from the ACS-IRG New Investigator Award in Cancer Research ( IRG-02-196 ), and from the Prostate Cancer Research Program (PCRP) – Impact Award – US Department of Defense ( W81XWH-17-1-0675 ). J.d.B. ( W81XWH-17-1-0676 ) and G.V.R. ( W81XWH-17-1-0674 ) acknowledges funding from the Prostate Cancer Research Program (PCRP) – Impact Award – US Department of Defense . The authors acknowledge funding from Prostate Cancer UK , the Prostate Cancer Foundation , Movember , Stand Up To Cancer , the US Department of Defense , Cancer Research UK , the UK Department of Health to the ICR/Royal Marsden ECMC , the Academy of Medical Sciences , and NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden and The Institute of Cancer Research . A.S. is supported by a Medical Research Council fellowship . S.B. is supported by grants from the NIH ( RO1CA149461 , RO1CA197796 , and R21CA202403 ) and the National Aeronautics and Space Administration ( NNX16AD78G ). C.-M.C. is supported by grants from the NIH ( CA103867 ), CPRIT ( RP140367 ), and the Welch Foundation ( I-1805 ). C.X. was partially supported by NIH grant UL1TR001105 . Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = jan,
day = "16",
doi = "10.1016/j.celrep.2017.12.078",
language = "English (US)",
volume = "22",
pages = "796--808",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}