BRD4 facilitates replication stress-induced DNA damage response

• Published in: Oncogene 2018-07, Vol.37 (28), p.3763-3777
• Main Authors: Zhang, Jingwen, Dulak, Austin M., Hattersley, Maureen M., Willis, Brandon S., Nikkilä, Jenni, Wang, Anderson, Lau, Alan, Reimer, Corinne, Zinda, Michael, Fawell, Stephen E., Mills, Gordon B., Chen, Huawei
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 13/95; 14; 14/1; 631/67/1517/1709; 631/80/86/2366; 82/29; 82/58; 96/2; 96/47; Animals; Antineoplastic agents; Apoptosis; Cancer; Cancer cells; Cancer prevention; Cancer treatment; Cell Biology; Cell Line, Tumor; Cellular proteins; CHK1 protein; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA Damage - drug effects; DNA Damage - genetics; DNA repair; DNA replication; DNA Replication - drug effects; DNA Replication - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genes; Health aspects; Heterocyclic Compounds, 2-Ring - pharmacology; Human Genetics; Humans; Innovations; Internal Medicine; Medicine; Medicine & Public Health; Mice; Mice, SCID; Nuclear Proteins - genetics; Oncology; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - genetics; Piperazines - pharmacology; Pyrimidines - pharmacology; Replication initiation; Signal Transduction - drug effects; Signal Transduction - genetics; Sulfoxides - pharmacology; Transcription; Transcription (Genetics); Transcription Factors - genetics; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0194-3

Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable part in DNA replication checkpoint signaling. Inhibition of BRD4 by JQ1 or AZD5153 resulted in a rapid, time-dependent reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Furthermore, BRD4 inhibition sensitized cancer cells to various replication stress-inducing agents, and synergized with ATR inhibitor AZD6738 to induce cell killing across a number of cancer cell lines. The synergistic interaction between AZD5153 and AZD6738 is translatable to in vivo ovarian cell-line and patient-derived xenograft models. Taken together, our study uncovers a new biological function of BRD4 and provides mechanistic rationale for combining BET inhibitors with DDR-targeted agents for cancer therapy.