TOP2A promotes non-small cell lung cancer progression via LDHA-mediated glycolysis and histone lactylation.

BACKGROUND: Topoisomerase 2-alpha (TOP2A) has been connected to a variety of cancers, but its role in non-small cell lung cancer (NSCLC) metabolism remains unclear. This study intended to investigate the involvement of glycolysis and histone lactylation in NSCLC advancement by exploring important regulators such as TOP2A and lactate dehydrogenase A (LDHA). METHODS: Bioinformatics analysis of The Cancer Genome Atlas (TCGA)-NSCLC, GSE33532, and GSE74706 datasets was performed to identify the hub gene TOP2A. The correlation between TOP2A and LDHA was then analyzed and their expression in NSCLC samples was verified. In vitro tests were conducted to study the expression and function of TOP2A by knockdown and overexpression experiments in NSCLC cells. Lactate generation, glucose absorption, and extracellular acidification rate (ECAR) were measured to evaluate glycolysis. Protein lactylation was assessed by western blot (WB) analysis. RESULTS: Expression analysis showed a significant positive correlation between TOP2A and LDHA, and both genes were upregulated in NSCLC samples. TOP2A knockdown prevented the invasion, migration, and proliferation of NSCLC cells while reducing glycolytic activity as manifested by decreased ECAR, glucose uptake, as well as lactate production. Mechanistically, TOP2A regulated histone lactylation by modulating P300 expression and LDHA-mediated lactate production. TOP2A silencing reduced pan-lysine acetylation and H3K18 lactylation levels. Importantly, TOP2A overexpression partially rescued the inhibitory consequences of glycolytic inhibitors on NSCLC cell function and protein lactylation. CONCLUSIONS: Our results indicate a new function for TOP2A in promoting NSCLC progression through modulating glycolysis and histone lactylation, suggesting TOP2A as a possible therapeutic target to treat NSCLC.