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.

• Authors: Xiangyi Li, GuemHee Baek, Susmita G Ramanand, Adam Sharp, Yunpeng Gao, Wei Yuan, Jon Welti, Daniel N Rodrigues, David Dolling, Ines Figueiredo, Semini Sumanasuriya, Mateus Crespo, Adam Aslam, Rui Li, Yi Yin, Bipasha Mukherjee, Mohammed Kanchwala, Ashley M Hughes, Wendy S Halsey, Cheng-Ming Chiang, Chao Xing, Ganesh V Raj, Sandeep Burma, Johann de Bono, Ram S Mani
• Journal: Cell reports (Cell Rep) Vol. 22 Issue 3 Pg. 796-808 (01 16 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29346775 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• BRD4 protein, human
• Cell Cycle Proteins
• Chromatin
• Histones
• Nuclear Proteins
• Oncogene Proteins, Fusion
• TMPRSS2-ERG fusion protein, human
• Transcription Factors

Topics

• Acetylation
• Cell Cycle Proteins
• Cell Line, Tumor
• Chromatin (genetics, metabolism)
• DNA Damage
• DNA End-Joining Repair
• Gene Fusion
• Gene Rearrangement
• Histones (genetics, metabolism)
• Humans
• Male
• Nuclear Proteins (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Transcription Factors (genetics, metabolism)