BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1

被引：81

作者：

Zhang, Zhenfeng ^{[1
,2
]}

Ma, Pengfei ^{[1
]}

Jing, Ying ^{[1
]}

Yan, Ying ^{[3
]}

Cai, Mei-Chun ^{[4
]}

Zhang, Meiying ^{[5
,6
]}

Zhang, Shengzhe ^{[7
,8
]}

Peng, Huixin ^{[1
]}

Ji, Zhi-Liang ^{[4
]}

Di, Wen ^{[5
,6
]}

Gu, Zhenyu ^{[3
]}

Gao, Wei-Qiang ^{[1
,7
,8
]}

Zhuang, Guanglei ^{[1
,6
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, State Key Lab Oncogenes & Related Genes,Renji Med, Shanghai 200030, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, State Key Lab Oncogenes & Related Genes,Shanghai, Shanghai 200030, Peoples R China

[3] GenenDesign Co Ltd, Shanghai, Peoples R China

[4] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen, Fujian, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Obstet & Gynecol, Shanghai 200030, Peoples R China

[6] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Shanghai Key Lab Gynecol Oncol, Shanghai 200030, Peoples R China

[7] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai 200030, Peoples R China

[8] Shanghai Jiao Tong Univ, Med Res Inst X, Shanghai 200030, Peoples R China

来源：

THERANOSTICS | 2016年 / 6卷 / 02期

基金：

中国国家自然科学基金;

关键词：

ovarian cancer; BET inhibitors; BRD4; FoxM1; SELECTIVE-INHIBITION; RANDOMIZED PHASE-2; CELL-LINES; CHROMATIN; GENOMICS; OLAPARIB; TARGET; MYC; DEPENDENCIES; SENSITIVITY;

D O I：

10.7150/thno.13178

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Ovarian cancer is responsible for the highest mortality among all gynecologic malignancies, and novel therapies are urgently needed to improve patient outcome. Here we performed an integrative genomic analysis and identified the bromodomain and extraterminal domain (BET) protein BRD4 as a potential therapeutic target in ovarian cancer. Suppression of BRD4 using small-molecule BET inhibitors JQ1 and I-BET151, or dual kinase-bromodomain inhibitor volasertib, led to robust and broad antitumor effects across all subclasses of ovarian cancer. In contrast to many other cancers which are susceptible to BET inhibition due to downregulation of super-enhancer-dependent MYC transcript, we discovered that JQ1-sensitive ovarian cancer cells exhibited marked disruption of Forkhead box protein M1 (FoxM1) pathway, a key driver of ovarian carcinoma. These in vitro findings were further supported by in vivo efficacies of JQ1 targeting both cell line-based and patient-derived xenograft models. Our data establish a new treatment strategy against ovarian cancer by employing epigenetic vulnerabilities, and provide a mechanistic rationale for the clinical investigation of BET bromodomain inhibitors in this deadly disease.

引用

页码：219 / 230

页数：12

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