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

Abstract

SummaryBRD4 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.

Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

“…Recently, BET inhibitors have been reported to hamper DNA damage repair through several distinct mechanisms. Li et al . reported that BRD4 participated in NHEJ DNA repair by regulating NHEJ DNA repair genes and interacting with NHEJ DNA repair proteins.…”

“…Recently, BET inhibitors have been reported to hamper DNA damage repair through several distinct mechanisms. Li et al 17 reported that BRD4 participated in NHEJ DNA repair by regulating NHEJ DNA repair genes and interacting with NHEJ DNA repair proteins. Wang et al 33 discovered a BRD-like module in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs-BRD) to which JQ1 could bind and further showed that JQ1 hampered NHEJ DNA repair by impairing DNA-PKcs activity.…”

“…Although the effect of BET inhibitors on the expression of oncogenes such as c‐Myc has been extensively addressed, the mechanisms by which BET inhibition produces cytotoxicity remain unknown. However, several recent studies have reported that BRD4 is essential for the repair of DNA double‐strand breaks (DSBs), and that BET inhibitors suppress both of the major DSB repair mechanisms, homologous recombination (HR) and nonhomologous end joining (NHEJ) …”

“…However, several recent studies have reported that BRD4 is essential for the repair of DNA double-strand breaks (DSBs), and that BET inhibitors suppress both of the major DSB repair mechanisms, homologous recombination (HR) and nonhomologous end joining (NHEJ). [15][16][17][18] The tyrosine kinase WEE1, which is a crucial component of the G2-M cell cycle checkpoint, prevents mitotic entry in response to cellular DNA damage by acting in cooperation with myelin transcription factor 1 (MYT1) kinase. WEE1 and MYT1 kinases inhibit CDK1 activity by phosphorylating CDK1 at Thr14 and Tyr15, which results in the activation of the G2-M checkpoint and cell cycle arrest.…”

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…Immunohistochemistry (IHC) for BRD4, AR-V7 and full length androgen receptor (AR-FL) was performed on patient samples and CP50 PDX as previously described (Supplementary Methods) (25,26,43).…”