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）是最常见的原发性脑肿瘤， 美国每年确诊8500例。在一段时间内， 一年后，几乎所有的病人都死于这种有害的疾病，尽管进行了治疗。 因此，新的，理想的肿瘤特异性方法是必要的，以打击这些 肿瘤的与其他恶性肿瘤相似，GBM依赖于有氧糖酵解，这意味着 矛盾的是，葡萄糖在存在大量 分子氧（Warburg效应）。基于染色质免疫沉淀 通过测序和转录组分析，我们发现通过 帕比司他、伏立诺他和FK228导致干细胞样代谢的重编程， 并建立GBM细胞，这部分是由三个关键的调节协调， 转录因子这导致糖酵解的显著减少（糖酵解的逆转）。 瓦尔堡效应），总体ATP水平较低。HDAC处理的GBM细胞重新激活 氧化磷酸化（OXPHOS）。一致，干扰线粒体 翻译或ATP产生增强干细胞样胶质瘤和患者的细胞凋亡 衍生的异种移植（PDX）细胞。为了给OXPHOS提供燃料，HDAC处理的胶质母细胞瘤细胞 增加与脂肪酸氧化有关的转运蛋白和酶的水平（粮农组织） 以及通过临床验证的化合物，依托莫西， 协同诱导PDX、干细胞样和已建立的胶质母细胞瘤细胞凋亡， 体外以及体内PDX模型。总的来说，这项研究将提高我们的 了解脑肿瘤的治疗，并可能使我们能够 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.