Quercetin enhances the anti-tumor effects of BET inhibitors by suppressing hnRNPA1

Thao N.D. Pham*, Sophie Stempel, Mario A. Shields, Christina Spaulding, Krishan Kumar, David J. Bentrem, Maria Matsangou, Hidayatullah G. Munshi

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Bromodomain and extraterminal domain (BET) proteins, which are important epigenetic readers, are often dysregulated in cancer. While a number of BET inhibitors are currently in early phase clinical trials, BET inhibitors show limited single-agent activity. The purpose of this study is to determine if Quercetin, a naturally occurring polyphenolic flavonoid often found abundant in fruits and vegetables, can enhance the anti-tumor effects of BET inhibitors. The efficacy of the combination was evaluated in vitro and in a xenograft model of pancreatic cancer. Co-treatment with BET inhibitors and Quercetin promoted apoptosis, decreased sphere-forming ability by cancer cells, and decreased cell proliferation. We found that hnRNPA1, a nuclear protein known to control mRNA export and mRNA translation of anti-apoptotic proteins, mediates some anti-tumor effects by Quercetin. Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin. Significantly, Quercetin decreased hnRNPA1 in vivo and enhanced the effects of BET inhibitors at suppressing tumor growth. Together, these results demonstrate that Quercetin enhances the efficacy of BET inhibitors by suppressing hnRNPA1, and identify combination therapy with Quercetin and BET inhibitors for the treatment of cancer patients.

Original languageEnglish (US)
Article number4293
JournalInternational journal of molecular sciences
Volume20
Issue number17
DOIs
StatePublished - Sep 1 2019

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Keywords

  • Bromodomain and extraterminal domain (BET) inhibitors
  • Combination therapy
  • Flavonoids
  • Heterogeneous nuclear nucleoprotein A1 (hnRNPA1)
  • Pancreatic cancer
  • Quercetin
  • Survivin
  • Thyroid cancer

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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