Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma

Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM. [Display omitted] •Lactate is metabolized in glioblastoma, which is dependent on cellular respiration•Lactate provides carbons to acetyl-residues of histones•Lactate modifies the enhancer and super-enhancer landscape of GBM cells Torrini and Nguyen et al. reveal an important role of lactate in a broad range of glioblastoma (GBM). They demonstrate that lactate is actively metabolized in a manner reliant on cellular respiration and that lactate affects gene expression through modulation of the epigenome. Thus, targeting oxidative metabolism and lactate metabolism may be a novel therapeutic approach for GBM.