The Oncogenic Regulation of Histone Lysine Lactylation

L-lactate is generated during glycolysis, a metabolic pathway that is widely associated with many physiological and disease related processes. We recently reported the discovery of lysine L-lactylation [K(L-la)] as a novel protein posttranslational modification occurring on histone proteins that can contribute to gene transcription. K(L-la) can be stimulated by L-lactate during macrophage polarization and a few types of differentiated culture cells. Excess L-lactate generation is a defining feature of cancer. However, it remains unknown if the elevated L-lactate in cancer cells will modulated histone K(L-la) that in turn regulate gene expression. Here, we report that the oncogenic signaling arising from the RAS-RAF-MAPK pathway can elevate histone K(L-la) levels through increased L-lactate synthesis stemming from the Warburg effect. Interestingly, the elevation of histone K(L-la) is correlated with intracellular lactate concentration in diverse types of cultured cancer cells. Inhibitors of key glycolysis enzymes regulates cellular lactate levels that in turn modulate histone K(L-la). Using quantitative proteomics, we demonstrate that distinct members of the MAPK pathway can differentially contribute to the abundance of specific histone K(L-la) sites. Lastly, we identify and validate MOF as a novel lactyltransferase both in vitro and in cells. Our study thus reveals that lysine L-lactylation is a histone mark that is dynamically regulated by oncogenic signals and MOF.