Cargando…
BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729770/ https://www.ncbi.nlm.nih.gov/pubmed/26877780 http://dx.doi.org/10.7150/thno.13178 |
_version_ | 1782412290333605888 |
---|---|
author | Zhang, Zhenfeng Ma, Pengfei Jing, Ying Yan, Ying Cai, Mei-Chun Zhang, Meiying Zhang, Shengzhe Peng, Huixin Ji, Zhi-Liang Di, Wen Gu, Zhenyu Gao, Wei-Qiang Zhuang, Guanglei |
author_facet | Zhang, Zhenfeng Ma, Pengfei Jing, Ying Yan, Ying Cai, Mei-Chun Zhang, Meiying Zhang, Shengzhe Peng, Huixin Ji, Zhi-Liang Di, Wen Gu, Zhenyu Gao, Wei-Qiang Zhuang, Guanglei |
author_sort | Zhang, Zhenfeng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4729770 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-47297702016-02-12 BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 Zhang, Zhenfeng Ma, Pengfei Jing, Ying Yan, Ying Cai, Mei-Chun Zhang, Meiying Zhang, Shengzhe Peng, Huixin Ji, Zhi-Liang Di, Wen Gu, Zhenyu Gao, Wei-Qiang Zhuang, Guanglei Theranostics Research Paper 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. Ivyspring International Publisher 2016-01-01 /pmc/articles/PMC4729770/ /pubmed/26877780 http://dx.doi.org/10.7150/thno.13178 Text en © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions. |
spellingShingle | Research Paper Zhang, Zhenfeng Ma, Pengfei Jing, Ying Yan, Ying Cai, Mei-Chun Zhang, Meiying Zhang, Shengzhe Peng, Huixin Ji, Zhi-Liang Di, Wen Gu, Zhenyu Gao, Wei-Qiang Zhuang, Guanglei BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 |
title | BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 |
title_full | BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 |
title_fullStr | BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 |
title_full_unstemmed | BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 |
title_short | BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1 |
title_sort | bet bromodomain inhibition as a therapeutic strategy in ovarian cancer by downregulating foxm1 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729770/ https://www.ncbi.nlm.nih.gov/pubmed/26877780 http://dx.doi.org/10.7150/thno.13178 |
work_keys_str_mv | AT zhangzhenfeng betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT mapengfei betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT jingying betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT yanying betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT caimeichun betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT zhangmeiying betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT zhangshengzhe betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT penghuixin betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT jizhiliang betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT diwen betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT guzhenyu betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT gaoweiqiang betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 AT zhuangguanglei betbromodomaininhibitionasatherapeuticstrategyinovariancancerbydownregulatingfoxm1 |