乳癌におけるヒストン乳酸化を介した細胞増殖を調節するPKM2-DNMT3A-SMAD2軸

Cancer develops from the unregulated proliferation of cells, influenced by a confluence of genetic mutations and epigenetic modifications that disrupt normal regulatory networks. In recent years, cellular metabolism has emerged as an important factor in controlling epigenetic states by connecting the availability of intracellular metabolites to changes in chromatin. One such metabolite is lactate, a glycolytic by-product produced in large amounts in tumor cells because of the Warburg effect. Lactate has been found to be a substrate for histone lactylation, a recently discovered epigenetic mark that affects gene expression. Although histone lactylation is gaining importance in cancer biology, its functional role in breast cancer remains inadequately elucidated. In this study, we utilized a lactate-deficient cell line created by the knockout of PKM2 to examine the effects of promoter-level histone H3 lysine 18 lactylation (H3K18la) on the regulation of the DNMT3A gene, which subsequently influences SMAD2 expression and modulates the TGF-β signaling pathway and cellular proliferation in breast cancer. Our findings elucidate a novel metabolic-epigenetic axis that cancer cells utilize to drive tumorigenesis.