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

被引：22

作者：

Pongas, Georgios ^{[1
]}

Kim, Marianne K. ^{[1
]}

Min, Dong J. ^{[2
]}

House, Carrie D. ^{[1
]}

Jordan, Elizabeth ^{[1
]}

Caplen, Natasha ^{[3
]}

Chakka, Sirisha ^{[3
]}

Ohiri, Joyce ^{[1
]}

Kruhlak, Michael J. ^{[4
]}

Annunziata, Christina M. ^{[1
]}

机构：

[1] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[2] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA

[3] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[4] NCI, Expt Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

来源：

ONCOTARGET | 2017年 / 8卷 / 31期

关键词：

heterochromatin; BRD4; CBX5; DNA repair; CHK1; BROMODOMAIN PROTEIN; OVARIAN-CANCER; IONIZING-RADIATION; THERAPEUTIC TARGET; BET BROMODOMAINS; CHK1; INHIBITOR; CARCINOMA; CHROMATIN; PROFILES; ACTIVATION;

D O I：

10.18632/oncotarget.17572

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (HP1 alpha) level. CHK1 inhibitor induced DDR marker, gamma-H2AX, but BRD4 suppression did not. Furthermore, nuclear localization of CBX5 and gamma-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.

引用

页码：51402 / 51415

页数：14

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