Oncotarget

Research Papers:

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 and Christina M. Annunziata _

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Oncotarget. 2017; 8:51402-51415. https://doi.org/10.18632/oncotarget.17572

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Abstract

Georgios Pongas1,*, Marianne K. Kim1,*, Dong J. Min2, Carrie D. House1, Elizabeth Jordan1, Natasha Caplen3, Sirisha Chakka3, Joyce Ohiri1, Michael J. Kruhlak4 and Christina M. Annunziata1

1Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

2Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

3Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

4Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

*These authors have contributed equally to this work

Correspondence to:

Christina M. Annunziata, email: annunzic@mail.nih.gov

Keywords: heterochromatin, BRD4, CBX5, DNA repair, CHK1

Received: April 26, 2016    Accepted: April 10, 2017    Published: May 03, 2017

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 (HP1α) 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.


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