HDAC Inhibitors Reverse the Warburg Effect and Elicit Metabolic Vulnerabilities in Model Systems of Glioblastoma

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.