Lactate epigenetically shapes tumor cell states in H3K27M diffuse midline gliomas

H3K27M diffuse midline gliomas (DMGs) are lethal and lack treatment options. These tumors exhibit tumor heterogeneity with aggressive oligodendrocyte precursor (OPC)- and mesenchymal (MES)-like cell states. Because all tumor cells bear H3K27M, tumor heterogeneity has been attributed to microenvironmental cues that remain obscure. H3K27M DMGs exhibit increased glycolysis and the Warburg effect to produce lactate. Lactate can directly modify histone lysines including H3K27Lac, and we hypothesized that lactate epigenetically regulates tumor cell states in H3K27M DMGs. We undertook a comprehensive and integrated analysis of H3K27M DMG cell lines, animal models, tumor tissues, and magnetic resonance spectroscopy in patients to decipher the epigenetic roles of lactate. Here, we report that H3K27M cells uniquely exhibit elevation of the activating mark H3K27Lac. We observed significant heterogeneity in lactate levels within tumors, and the addition of exogenous lactate resulted in marked increases in H3K27Lac and the expression of critical OPC- and MES- like gene signature genes, which correlates with poorer patient outcomes. Our therapeutic approach leverages the inhibition of CBP/p300, which deposits both H3K27Lac and H3K27ac. Targeting CBP/p300 effectively reduces both H3K27Lac and H3K27ac levels, suppresses key OPC- and MES-like signatures, and shows efficacy in preclinical models. Collectively, our findings identify lactate as a key player in the epigenetic regulation of tumor cell state heterogeneity and suggest that targeting this pathway offers promise for addressing the heterogeneous complexities of H3K27M DMGs.