BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.
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Authors
Li, X
Baek, G
Ramanand, SG
Sharp, A
Gao, Y
Yuan, W
Welti, J
Rodrigues, DN
Dolling, D
Figueiredo, I
Sumanasuriya, S
Crespo, M
Aslam, A
Li, R
Yin, Y
Mukherjee, B
Kanchwala, M
Hughes, AM
Halsey, WS
Chiang, C-M
Xing, C
Raj, GV
Burma, S
de Bono, J
Mani, RS
Baek, G
Ramanand, SG
Sharp, A
Gao, Y
Yuan, W
Welti, J
Rodrigues, DN
Dolling, D
Figueiredo, I
Sumanasuriya, S
Crespo, M
Aslam, A
Li, R
Yin, Y
Mukherjee, B
Kanchwala, M
Hughes, AM
Halsey, WS
Chiang, C-M
Xing, C
Raj, GV
Burma, S
de Bono, J
Mani, RS
Document Type
Journal Article
Date
2018-01-16
Date Accepted
2017-12-21
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.
Citation
Cell reports, 2018, 22 (3), pp. 796 - 808
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Prostate Cancer Targeted Therapy Group
Translational Therapeutics