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

Cell Reports

David Dolling¹  Yunpeng Gao²  Ram S. Mani²  GuemHee Baek²  Adam Aslam²  Xiangyi Li²  Susmita G. Ramanand²  Sandeep Burma³  Bipasha Mukherjee³  Ganesh V. Raj⁴  Yi Yin⁴  Rui Li⁴  Chao Xing⁵  Mohammed Kanchwala⁵  Cheng-Ming Chiang⁶  Semini Sumanasuriya⁷  Mateus Crespo⁷  Johann de Bono⁷  Daniel N. Rodrigues⁷  Ines Figueiredo⁷  Adam Sharp⁷  Jon Welti⁷  Wei Yuan⁷  Ashley M. Hughes⁸  Wendy S. Halsey⁸ 

[1] Clinical Trials and Statistics Unit, Institute of Cancer Research, London SM2 5NG, UK;Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA;Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA;Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA;Eugene McDermott Center for Human Growth & Development, UT Southwestern Medical Center, Dallas, TX 75390, USA;Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA;Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK;Target Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA;

关键词: BRD4;    BRD2;    DNA repair;    non-homologous end joining;    NHEJ;    gene fusion;    genomic rearrangements;    TMPRSS2-ERG;    prostate cancer;    CRPC;   

DOI  :  10.1016/j.celrep.2017.12.078

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown