Abstract
A previously unknown histone modification, lysine lactylation, was found in mouse and human cells.
Major Finding: A previously unknown histone modification, lysine lactylation, was found in mouse and human cells.
Concept: M1 macrophage polarization increased histone lactylation, increasing expression of M2-like genes.
Impact: Investigation of the potential consequences of histone lactylation in cancer is of interet.
Histone modifications, such as methylation and acetylation, are key regulators of gene expression, and some dysfunctional histone-modification patterns promote cancer. In human and mouse cells, Zhang, Tang, and colleagues identified histone lysine lactylation (Kla), a previously unrecognized histone modification. Both high-performance liquid chromatography–tandem mass spectrometry experiments and immunoblotting with a pan-Kla antibody supported the existence of Kla in cells. Extracellular lactate was able to stimulate histone lactylation, and exposure of cells to glucose (from which most intracellular lactate is derived) revealed that histone Kla levels were increased by glucose in a dose-dependent fashion. In accordance with this finding, inhibitors of intracellular lactate production reduced histone Kla levels, whereas a compound that inhibits glycolysis (thus increasing intracellular lactate concentrations) increased histone Kla levels. Demonstrating the potential physiologic relevance of these results, hypoxia, which causes increased levels of intracellular lactate by enhancing glycolysis, was associated with an increase in histone Kla levels. Further, intracellular lactate and histone Kla levels were increased following M1 macrophage polarization, a process that involves a switch to aerobic glycolysis. The increase in histone Kla levels in this context had a functional consequence—an induction of M2-like genes in the M1 macrophages. Experiments in which lactate levels during M1 polarization were manipulated supported the observed role of intracellular lactate and histone Kla levels in promoting the expression of M2-like genes during M1 polarization. In summary, this study robustly demonstrates the presence and relevance of a previously unidentified histone modification, which may be important both during normal cellular processes and in cancer.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.