Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer

Lactate has been observed to fuel TCA cycle and is associated with cancer progression in human lung cancer, the leading cause of cancer deaths worldwide, but the effect of lactate on lung cancer metabolism is rarely reported. In this study, disordered metabolism in non-small cell lung cancer was demonstrated by increased G6PD and SDHA protein levels via immunofluorescence, and up-regulated lactate dehydrogenase was found to be associated with poor prognosis. Then flow cytometry and Seahorse XFe analyzer were utilized to detect the effect of lactate on glycolysis and mitochondrial function in non-small cell lung cancer cells. The results show that in non-small cell lung cancer cells lactate attenuates glucose uptake and glycolysis while maintaining mitochondrial homeostasis as indicated by improved mitochondrial membrane potential. Further exploration found that mRNA levels of glycolytic enzymes (HK-1, PKM) and TCA cycle enzymes (SDHA, IDH3G) are respectively down-regulated and up-regulated by lactate, and increased histone lactylation was observed in promoters of HK-1 and IDH3G via chromatin immunoprecipitation assay. Taken together, the above results indicate that lactate modulates cellular metabolism at least in part through histone lactylation-mediated gene expression in non-small cell lung cancer.