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.

中文翻译：

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BRD4和HDAC3抑制剂的组合通过阻断GLI1/IL-6/STAT3信号轴协同抑制胶质瘤干细胞生长

胶质瘤干细胞 (GSC) 对肿瘤维持、侵袭和复发至关重要。使用带有 shRNA 文库的全球表观遗传筛选，我们将 HDAC3 确定为 GSC 干性的一个重要因素。在这里，我们证明了 GSC 对 HDAC3 抑制剂 RGFP966 (HDAC3i) 的反应很差，这是由于 IL6 和 STAT3 激活的产生。为了增强 GSC 对 HDAC3i 的敏感性，我们探讨了在 GSC 中与 BRD4 抑制剂 JQ1 (BRD4i) 共同处理是否产生更好的抗肿瘤效果。BRD4i 与 HDAC3i 协同抑制 GSC 生长。HDAC3 抑制上调 H3K27 的乙酰化，这使得 BRD4 募集到 GLI1 基因启动子并诱导其表达。GLI1 是一种转录因子，它开启 IL6 的表达，从而导致 STAT3 信号通路的激活。然而，BRD4i 抑制 GLI1 基因的转录，从而阻断 GLI1/IL6/STAT3 通路。在体内，HDAC3i/BRD4i 组合比单独使用任一药物引起更强的肿瘤生长抑制。因此，HDAC3i/BRD4i 可能为 GBM 提供有希望的疗法。