胶质1
车站3
癌症研究
生物
转录因子
细胞生长
表观遗传学
HDAC3型
信号转导
下调和上调
细胞生物学
组蛋白
组蛋白脱乙酰基酶
基因
刺猬信号通路
遗传学
作者
Qian Wang,Shengnan Jia,Ding Wang,Xuyang Chen,Dhan V. Kalvakolanu,Hongwu Zheng,Xiaodong Wei,Naiyan Wen,Hang Liang,Baofeng Guo,Ling Zhang
标识
DOI:10.1158/1535-7163.mct-20-0037
摘要
Abstract Glioma stem cells (GSC) are essential for tumor maintenance, invasiveness, and recurrence. Using a global epigenetic screening with an shRNA library, we identified HDAC3 as an essential factor for GSC stemness. Here, we demonstrated that GSCs poorly respond to an HDAC3 inhibitor, RGFP966 (HDAC3i), owing to the production of IL6 and STAT3 activation. To enhance GSC sensitivity to HDAC3i, we explored whether cotreatment with a BRD4 inhibitor, JQ1 (BRD4i), in GSCs produced a better antitumor effect. BRD4i synergistically inhibits GSC growth in association with HDAC3i. HDAC3 inhibition upregulated the acetylation of H3K27, which allowed the recruitment of BRD4 to the GLI1 gene promoter and induced its expression. GLI1, a transcription factor, turned on the expression of IL6, which led to the activation of STAT3 signaling pathways. However, BRD4i inhibited transcription of the GLI1 gene, thereby blocking the GLI1/IL6/STAT3 pathway. In vivo, the HDAC3i/BRD4i combination caused stronger tumor growth suppression than either drug alone. Thus, HDAC3i/BRD4i might provide promising therapies for GBM.
科研通智能强力驱动
Strongly Powered by AbleSci AI