BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.

Autor:	Li X; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Baek G; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Ramanand SG; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Sharp A; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Gao Y; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Yuan W; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Welti J; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Rodrigues DN; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Dolling D; Clinical Trials and Statistics Unit, Institute of Cancer Research, London SM2 5NG, UK., Figueiredo I; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Sumanasuriya S; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Crespo M; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Aslam A; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Li R; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Yin Y; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Mukherjee B; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Kanchwala M; Eugene McDermott Center for Human Growth & Development, UT Southwestern Medical Center, Dallas, TX 75390, USA., Hughes AM; Target Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA., Halsey WS; Target Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA., Chiang CM; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Xing C; Eugene McDermott Center for Human Growth & Development, UT Southwestern Medical Center, Dallas, TX 75390, USA., Raj GV; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Burma S; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA., de Bono J; Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK., Mani RS; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ram.mani@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2018 Jan 16; Vol. 22 (3), pp. 796-808.
DOI:	10.1016/j.celrep.2017.12.078
Abstrakt:	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. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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