RGFP966，一种组蛋白去乙酰化酶 3 抑制剂，通过阻断 TGF-β 信号通路中的 SMAD7 来促进神经胶质瘤干细胞分化。
RGFP966, a histone deacetylase 3 inhibitor, promotes glioma stem cell differentiation by blocking TGF-β signaling via SMAD7.
机构信息
Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, PR China.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
出版信息
Biochem Pharmacol. 2020 Oct;180:114118. doi: 10.1016/j.bcp.2020.114118. Epub 2020 Jun 23.
Glioma stem cells (GSC) play a major role in drug resistance and tumor recurrence. Using a genetic screen with a set of shRNAs that can target chromatin regulators in a GSC model, we have HDAC3 as a major negative regulator of GSC differentiation. Inhibition of HDAC3 using a pharmacological inhibitor or a siRNA led to the induction of GSC differentiation into astrocytes. Consequently, HDAC3-inhibition also caused a strong reduction of tumor-promoting and self-renewal capabilities of GSCs. These phenotypes were highly associated with an increased acetylation of SMAD7, which protected its ubiquitination. SMAD7 inhibits a TGF-β signaling axis that is required for maintaining stemness. These results demonstrate that HDAC3 appears to be a proper target in anti-glioma therapy.
神经胶质瘤干细胞（GSC）在耐药性和肿瘤复发中起主要作用。使用一组可以靶向 GSC 模型中染色质调节剂的 shRNA 进行遗传筛选，我们发现 HDAC3 是 GSC 分化的主要负调控因子。使用药理抑制剂或 siRNA 抑制 HDAC3 可诱导 GSC 分化为星形胶质细胞。因此，HDAC3 抑制也导致 GSCs 的促肿瘤和自我更新能力大幅降低。这些表型与 SMAD7 的乙酰化增加高度相关，这保护了其泛素化。SMAD7 抑制 TGF-β 信号通路，该通路对于维持干细胞特性是必需的。这些结果表明，HDAC3 似乎是抗神经胶质瘤治疗的合适靶标。
Zotero 插件