Department of General Surgery, the Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221002, PR China; Institute of Digestive Disease, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, Jiangsu 221002, PR China.
Department of General Surgery, the Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221002, PR China; Institute of Digestive Disease, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, Jiangsu 221002, PR China.
Eur J Pharmacol. 2019 Jun 5;852:189-197. doi: 10.1016/j.ejphar.2019.03.018. Epub 2019 Mar 12.
The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a potential target for cancer therapy. However, BRD4 roles in regulating the stemness of gastric cancer cells are unclear. Here, we demonstrated that BRD4 expression was significantly increased in gastric cancer tissues, cell spheroids, and BRD4 knockdown attenuated the stemness of gastric cancer cells characterized as the decrease of stemness markers expression, capacity of cells spheroids formation and ALDH1 activity. Importantly, BRD4 expression was negatively correlated with overall survival, first progression survival and post progression survival of gastric cancer patients. Mechanistic investigations revealed that miR-216a-3p was the most remarkably upregulated miRNA in response to BRD4 knockdown and Wnt/β-catenin signaling was necessary for BRD4-mediated promotion on the stemness of gastric cancer cells. Additionally, BRD4 directly bound to the promoter and promoted the methylation level of MIR216A promoter, thus decreasing miR-216a-3p level. Notably, Wnt3a was identified as the direct target of miR-216a-3p in gastric cancer cells. Therefore, our results defined a BRD4/miR-216a-3p/Wnt/β-catenin pathway in regulating the stemness of gastric cancer cells.
溴结构域和末端外结构域（BET）蛋白 BRD4 作为癌症治疗的潜在靶点正在兴起。然而，BRD4 在调节胃癌细胞干性中的作用尚不清楚。在这里，我们证明 BRD4 表达在胃癌组织、细胞球和 BRD4 敲低中显著增加，这削弱了胃癌细胞的干性，其特征是干性标志物表达、细胞球形成能力和 ALDH1 活性降低。重要的是，BRD4 表达与胃癌患者的总生存期、首次进展生存期和后进展生存期呈负相关。机制研究表明，miR-216a-3p 是对 BRD4 敲低反应最显著上调的 miRNA，Wnt/β-catenin 信号通路是 BRD4 介导的促进胃癌细胞干性所必需的。此外，BRD4 直接结合启动子并促进 MIR216A 启动子的甲基化水平，从而降低 miR-216a-3p 水平。值得注意的是，Wnt3a 被确定为胃癌细胞中 miR-216a-3p 的直接靶标。因此，我们的结果定义了 BRD4/miR-216a-3p/Wnt/β-catenin 通路在调节胃癌细胞干性中的作用。
