BRD4 facilitates DNA damage response and represses CBX5/ Heterochromatin protein 1 (HP1)

Georgios Pongas, Marianne K. Kim, Dong J. Min, Carrie D. House, Elizabeth Jordan, Natasha Caplen, Sirisha Chakka, Joyce Ohiri, Michael J. Kruhlak, Christina M. Annunziata

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Ovarian cancer (OC) is a heterogeneous disease characterized by defective DNA repair. Very few targets are universally expressed in the high grade serous (HGS) subtype. We previously identified that CHK1 was overexpressed in most of HGSOC. Here, we sought to understand the DNA damage response (DDR) to CHK1 inhibition and increase the anti-tumor activity of this pathway. We found BRD4 suppression either by siRNA or BRD4 inhibitor JQ1 enhanced the cytotoxicity of CHK1 inhibition. Interestingly, BRD4 was amplified and/or upregulated in a subset of HGSOC with statistical correlation to overall survival. BRD4 inhibition increased CBX5 (HP1a) level. CHK1 inhibitor induced DDR marker, γ-H2AX, but BRD4 suppression did not. Furthermore, nuclear localization of CBX5 and γ-H2AX was mutually exclusive in BRD4-and CHK1-inhibited cells, suggesting BRD4 facilitates DDR by repressing CBX5. Our results provide a strong rationale for clinical investigation of CHK1 and BRD4 co-inhibition, especially for HGSOC patients with BRD4 overexpression.

Original languageEnglish (US)
Pages (from-to)51402-51415
Number of pages14
JournalOncotarget
Volume8
Issue number31
DOIs
StatePublished - Feb 7 2017
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by Amgen Ovarian Cancer Research Grant (MK) from the Foundation for Women's Cancer, and by the Intramural Research Program, Center for Cancer Research, National Cancer Institute (CMA).

Publisher Copyright:
© Pongas et al.

Keywords

  • BRD4
  • CBX5
  • CHK1
  • DNA repair
  • Heterochromatin

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