High-grade gliomas (HGG) afflict both children and adults and respond poorly to current therapies. Epigenetic regulators have a role in gliomagenesis, but a broad, functional investigation of the impact and role of specific epigenetic targets has not been undertaken. Using a two-step, in vitro/in vivo epigenomic shRNA inhibition screen, we determine the chromatin remodeler BPTF to be a key regulator of adult HGG growth. We then demonstrate that BPTF knockdown decreases HGG growth in multiple pediatric HGG models as well. BPTF appears to regulate tumor growth through cell self-renewal maintenance, and BPTF knockdown leads these glial tumors toward more neuronal characteristics. BPTF's impact on growth is mediated through positive effects on expression of MYC and MYC pathway targets. HDAC inhibitors synergize with BPTF knockdown against HGG growth. BPTF inhibition is a promising strategy to combat HGG through epigenetic regulation of the MYC oncogenic pathway.

中文翻译：

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BPTF 通过 MYC 通路调节成人和儿童高级别胶质瘤的生长。

高级别神经胶质瘤 (HGG) 折磨着儿童和成人，并且对目前的疗法反应不佳。表观遗传调节因子在胶质瘤形成中发挥作用，但尚未对特定表观遗传靶点的影响和作用进行广泛的功能性研究。使用两步体外/体内表观基因组 shRNA 抑制筛选，我们确定染色质重塑剂 BPTF 是成人 HGG 生长的关键调节因子。然后，我们证明 BPTF 敲低也会降低多个儿科 HGG 模型中的 HGG 生长。BPTF 似乎通过细胞自我更新维持来调节肿瘤生长，而 BPTF 敲低导致这些神经胶质肿瘤具有更多的神经元特征。BPTF 对生长的影响是通过对 MYC 和 MYC 通路靶标表达的积极影响来介导的。HDAC 抑制剂与 BPTF 敲除协同作用以抑制 HGG 生长。BPTF 抑制是通过 MYC 致癌途径的表观遗传调控来对抗 HGG 的一种有前途的策略。