Lysine-specific histone demethylase 5A (KDM5A) is known to facilitate proliferation in cancer cells and maintain stemness to repress the astrocytic differentiation of neural stem cells (NSCs). In the study presented here, we investigated the effect of a KDM5 inhibitor, CPI-455, on NSC fate control. CPI-455 induced astrocytogenesis in NSCs during differentiation. Kdm5a, but not Kdm5c, knockdown induced glial fibrillary acidic protein (Gfap) transcription. CPI-455 induced signal transducer and activator of transcription 3, increased bone morphogenetic protein 2 expression, and enhanced mothers against decapentaplegic homolog 1/5/9 phosphorylation. The treatment of CPI-455 enhanced the methylation of histone H3 lysine 4 in the Gfap promoter when compared to that of the dimethyl sulfoxide control. In addition, CPI-455 treatment significantly reduced the recruitment of KDM5A to the Gfap promoter. Our data suggest that the KDM5 inhibitor CPI-455 effectively controls NSC cell fate via KDM5A inhibition and induces astrocytogenesis.

中文翻译：

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组蛋白赖氨酸脱甲基酶 KDM5 抑制剂 CPI-455 诱导神经干细胞星形细胞生成

赖氨酸特异性组蛋白去甲基化酶 5A (KDM5A) 已知可促进癌细胞增殖并维持干性，从而抑制神经干细胞 (NSC) 的星形胶质细胞分化。在此介绍的研究中，我们研究了 KDM5 抑制剂 CPI-455 对 NSC 命运控制的影响。 CPI-455 在分化过程中诱导 NSC 星形细胞生成。Kdm5a（而非Kdm5c）敲低可诱导神经胶质纤维酸性蛋白( Gfap ) 转录。 CPI-455 诱导信号转导子和转录激活子 3，增加骨形态发生蛋白 2 的表达，并增强母亲对十肢麻痹同源物 1/5/9 磷酸化的抵抗力。与二甲亚砜对照相比，CPI-455 的处理增强了Gfap启动子中组蛋白 H3 赖氨酸 4 的甲基化。此外，CPI-455 处理显着减少了 KDM5A 向Gfap启动子的募集。我们的数据表明，KDM5 抑制剂 CPI-455 通过 KDM5A 抑制有效控制 NSC 细胞命运并诱导星形细胞生成。