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.

Recently, the combination of androgen deprivation therapy (ADT) and radiation therapy (RT) has been shown to block the androgen receptor (AR)-driven DNA damage response (DDR) and enhance RT-mediated cell kill of prostate cancer (PCa). Since ADT may induce expression of AR splice variants (ARVs) we hypothesized that ARVs can drive DDR and mediate resistance to combined ADT and RT. Herein, we demonstrate that ARVs can increase the clonogenic survival of PCa cells following RT in an ADT-independent manner. RT induces the interaction between ARVs and a DDR driver, the DNA-dependent protein kinase catalytic subunit (DNA-PKc). Pharmacological inhibition of DNA-PKc blocks its interaction with ARVs and results in persistence of DNA damage, increased tumor cell kill and improved PCa cell survival following RT. These results indicate that combinatorial targeting of DNA-PKc with ADT and RT may be an effective strategy for overcoming radioresistance when treating clinically localized PCa.

Oncology, Taiho, Pfizer, and Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair-defective cancers, and PI3K/ AKT pathway inhibitors (no personal income). JDB was named an inventor, with no financial interest, for US patent 8,822,438 ("Methods and compositions for treating cancer"). He has been the co-investigator or principal investigator of many industry-sponsored clinical trials.

Background & Aims Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. Methods We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. Results The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (eg. IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL cells and of primary LPCs from wild-type mice, but not STAT1−/− or IRF-1−/− mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. Conclusion IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.