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

Xiangyi Li, Guem Hee 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 ChiangChao Xing, Ganesh V. Raj, Sandeep Burma, Johann de Bono, Ram S. Mani

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)796-808
Number of pages13
JournalCell Reports
Volume22
Issue number3
DOIs
StatePublished - Jan 16 2018

Keywords

  • BRD2
  • BRD4
  • CRPC
  • DNA repair
  • gene fusion
  • genomic rearrangements
  • NHEJ
  • non-homologous end joining
  • prostate cancer
  • TMPRSS2-ERG

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Li, X., Baek, G. H., Ramanand, S. G., Sharp, A., Gao, Y., Yuan, W., Welti, J., Rodrigues, D. N., Dolling, D., Figueiredo, I., Sumanasuriya, S., Crespo, M., Aslam, A., Li, R., Yin, Y., Mukherjee, B., Kanchwala, M., Hughes, A. M., Halsey, W. S., ... Mani, R. S. (2018). BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Cell Reports, 22(3), 796-808. https://doi.org/10.1016/j.celrep.2017.12.078