BRD4 promotes glioma cell stemness via enhancing miR-142-5p-mediated activation of Wnt/β-catenin signaling
BRD4 promotes glioma cell stemness via enhancing miR-142-5p-mediated activation of Wnt/β-catenin signaling
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DOI：
10.1002/tox.22873
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发表时间：
2019-11-14
影响因子：
4.5
通讯作者：
Dong, Danfeng
中科院分区：
文献类型：
--
作者：
Wang, Jubo;Quan, Yu;Dong, Danfeng
布罗莫结构域蛋白BRD 4在许多癌症中发挥致癌作用。然而，其在胶质瘤发生中的作用仍不清楚。在此，发现BRD 4表达在胶质瘤组织中增加，并且与胶质瘤患者的总体存活率负相关。我们构建细胞实验表明，BRD 4促进胶质瘤细胞的干性通过分析ALDH 1活性，主干性调节剂的表达，和球形成能力。从机制上讲，BRD 4敲低触发了miR-142- 5 p启动子甲基化的转换，其靶向Wnt 3a，从而进一步灭活Wnt/β-连环蛋白信号传导。重要的是，miR-142- 5 p的抑制或Wnt/β-连环蛋白信号传导的再激活挽救了BRD 4敲低对胶质瘤细胞干细胞性的抑制。因此，这些结果不仅表明BRD 4、miR-142- 5 p和Wnt/β-连环蛋白信号传导之间存在不可预见的联系，而且还揭示了一种有希望的基于表观遗传学的治疗策略，可能用于神经胶质瘤患者。
The bromodomain protein BRD4 exerts carcinogenic effects in many cancers. However, its roles in glioma occurrence are still confused. Here, it is found that BRD4 expression is increased in glioma tissues and negatively correlated with the overall survival of glioma patients. We construct cellular experiments indicating that BRD4 promotes glioma cell stemness by analyzing ALDH1 activity, master stemness regulator expression, and sphere formation ability. Mechanistically, BRD4 knockdown triggers a switch of miR-142-5p promoter methylation, which targets Wnt3a and thus further inactivates Wnt/beta-catenin signaling. Importantly, inhibition of miR-142-5p or reactivation of Wnt/beta-catenin signaling rescues the inhibition of BRD4 knockdown on glioma cell stemness. As a result, these results not only indicate an unforeseen connection between BRD4, miR-142-5p, and Wnt/beta-catenin signaling, but also reveal a promising epigenetic-based therapeutic strategy that might be explored for glioma patients.