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

Theranostics. 2016 Jan 1;6(2):219-30. doi: 10.7150/thno.13178. eCollection 2016.


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.

Keywords: BET inhibitors; BRD4; FoxM1; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Azepines / pharmacology
  • Azepines / therapeutic use
  • Carcinoma / drug therapy*
  • Cell Line, Tumor
  • Down-Regulation
  • Female
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Pteridines / pharmacology
  • Pteridines / therapeutic use
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Triazoles / pharmacology
  • Triazoles / therapeutic use


  • (+)-JQ1 compound
  • Antineoplastic Agents
  • Azepines
  • BI 6727
  • Brd4 protein, mouse
  • Forkhead Box Protein M1
  • Foxm1 protein, mouse
  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • Nuclear Proteins
  • Pteridines
  • Transcription Factors
  • Triazoles