Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
Int J Mol Sci. 2019 Sep 2;20(17):4293. doi: 10.3390/ijms20174293.
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.
溴结构域和末端外结构域（BET）蛋白是重要的表观遗传读码器，在癌症中常失调。虽然目前有许多 BET 抑制剂处于早期临床试验阶段，但 BET 抑制剂的单药活性有限。本研究旨在确定槲皮素（一种天然存在的多酚类黄酮，在水果和蔬菜中含量丰富）是否可以增强 BET 抑制剂的抗肿瘤作用。在体外和胰腺癌异种移植模型中评估了联合治疗的效果。BET 抑制剂和槲皮素联合治疗可促进细胞凋亡、降低癌细胞的球体形成能力和细胞增殖。我们发现 hnRNPA1（一种已知可控制 mRNA 输出和抗凋亡蛋白的 mRNA 翻译的核蛋白）介导了槲皮素的一些抗肿瘤作用。此外，我们还表明，BET 抑制剂与槲皮素或 hnRNPA1 敲低联合使用可降低抗凋亡蛋白 Survivin。重要的是，槲皮素在体内降低了 hnRNPA1，并增强了 BET 抑制剂抑制肿瘤生长的效果。总之，这些结果表明，槲皮素通过抑制 hnRNPA1 增强了 BET 抑制剂的疗效，并确定了槲皮素与 BET 抑制剂联合治疗癌症患者的方法。
