Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism

Abstract

Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, ¹³C₃-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism–epigenetics axis controlled by the cell’s own status or the environmental status.

Epigenetics: Lactate implicated in DNA-winding dynamics

Previously regarded as a metabolic byproduct, lactate plays an unexpected role in the modification of DNA-winding proteins called histones. A team led by Sunghyouk Park from Seoul National University, South Korea, showed that lactate serves as a major carbon source for the addition of acetyl groups to histones, an epigenetic modification that alters the coiling of DNA in ways that affect gene expression and can play a crucial role in disease development. The researchers found that lactate, produced during high-energy demand conditions, helps to drive this process with the aid of the enzyme lactate dehydrogenase, which is found in abundance in the nucleus of pancreatic cancer cells. The team’s findings establish a vital link between cellular metabolism and epigenetic regulation, opening potential avenues for targeted anti-cancer therapies that disrupt lactate-mediated acetylation or target the enzyme.