Glioblastoma (GBM) is a uniformly lethal disease driven by glioma stem cells (GSCs). Here, we use a chemical biology approach to unveil previously unknown GBM dependencies. By studying sulconazole (SN) with anti-GSC properties, we find that SN disrupts biotin distribution to the carboxylases and histones. Transcriptomic and metabolomic analyses of SN-treated GSCs reveal metabolic alterations that are characteristic of biotin-deficient cells, including intracellular cholesterol depletion, impairment of oxidative phosphorylation, and energetic crisis. Furthermore, SN treatment reduces histone biotinylation, histone acetylation, and expression of superenhancer-associated GSC critical genes, which are also observed when biotin distribution is genetically disrupted by holocarboxylase synthetase (HLCS) depletion. HLCS silencing impaired GSC tumorigenicity in an orthotopic xenograft brain tumor model. In GBM, high HLCS expression robustly indicates a poor prognosis. Thus, the dependency of GBM on biotin distribution suggests that the rational cotargeting of biotin-dependent metabolism and epigenetic pathways may be explored for GSC eradication.

中文翻译：

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化学生物学方法揭示了胶质母细胞瘤对生物素分布的依赖性

胶质母细胞瘤 (GBM) 是一种由胶质瘤干细胞 (GSC) 驱动的致死性疾病。在这里，我们使用化学生物学方法来揭示以前未知的 GBM 依赖性。通过研究具有抗 GSC 特性的磺康唑 (SN)，我们发现 SN 会破坏生物素向羧化酶和组蛋白的分布。经 SN 处理的 GSC 的转录组学和代谢组学分析揭示了生物素缺乏细胞特有的代谢改变，包括细胞内胆固醇消耗、氧化磷酸化受损和能量危机。此外，SN 处理减少了组蛋白生物素化、组蛋白乙酰化和超增强子相关 GSC 关键基因的表达，当生物素分布因全羧化酶合成酶 (HLCS) 耗竭而基因中断时，也会观察到这些情况。HLCS silencing impaired GSC tumorigenicity in an orthotopic xenograft brain tumor model. In GBM, high HLCS expression robustly indicates a poor prognosis. Thus, the dependency of GBM on biotin distribution suggests that the rational cotargeting of biotin-dependent metabolism and epigenetic pathways may be explored for GSC eradication.