HDAC inhibitors reverse the Warburg Effect and Elicit Metabolic Vulnerabilities in Model Systems of Glioblastoma

多形性胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，约 在美国，每年有8500例确诊病例。在一段时间内 有一年，尽管接受了治疗，几乎所有的患者都死于这种有害的疾病。 因此，有必要采用新的、理想的肿瘤特异性方法来对抗这些疾病。 肿瘤。与其他恶性肿瘤类似，基底膜依赖于有氧糖酵解，这意味着 自相矛盾的是，葡萄糖在大量的 分子氧(沃堡效应)。基于染色质免疫沉淀 测序和转录组分析，我们发现HDAC-抑制通过 Panobinostat、Vorinostat和FK228导致茎状细胞代谢的重新编程 并建立了GBM信元，该信元部分由三个键的调制来协调 转录因子。这导致糖酵解显著减少(逆转 华宝效应)，总体ATP水平较低。HDAC处理的GBM细胞重新激活 氧化磷酸化(OXPHOS)。一直以来，对线粒体的干扰 翻译或ATP产生促进干样胶质瘤和患者的细胞凋亡 来源异种移植(PDX)细胞。为OXPHOS、HDAC处理的胶质母细胞瘤细胞提供燃料 提高与脂肪酸氧化有关的转运蛋白和酶的水平(粮农组织) 以及临床验证化合物依托莫西对粮农组织的药理抑制作用， 协同诱导PDX、干细胞型和已建立的胶质母细胞瘤细胞凋亡 体外以及体内的PDX模型。总的来说，这项研究将增强我们的 对脑瘤治疗的了解，可能会让我们 为胶质母细胞瘤和其他胶质瘤制定新的治疗策略。

Glioblastoma multiforme (GBM) is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of roughly one year almost all patients succumb to this detrimental disease despite treatment. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. Akin to other malignancies, GBMs depend on aerobic glycolysis, meaning that paradoxically glucose is metabolized to lactate in the presence of an abundance of molecular oxygen (Warburg-effect). Based on a chromatin immunoprecipitation sequencing and transcriptome analysis, we found that HDAC-inhibition through panobinostat, vorinostat and FK228 results in reprogramming of metabolism in stem-like and established GBM cells, which is orchestrated in part by the modulation of three key transcription factors. This leads to a significant reduction of glycolysis (reversal of the Warburg effect) with lower overall ATP levels. HDAC treated GBM cells reactivate oxidative phosphorylation (OXPHOS). Consistently, interference with mitochondrial translation or ATP production enhanced apoptosis in stem-like glioma and patient derived xenograft (PDX) cells. To fuel OXPHOS, HDAC treated glioblastoma cells increased the levels of transporters and enzymes related to fatty acid oxidation (FAO) and pharmacological inhibition of FAO by the clinically validated compound, Etomoxir, synergistically induced apoptosis in PDX, stem-like and established glioblastoma cells in vitro as well as in PDX models in vivo. Overall, this research will enhance our understanding about the treatment of brain tumors and may potentially allow us to formulate a novel treatment strategy for glioblastomas and other gliomas.