KAT2A accelerates lung cancer progression through succinylation of TGFβR2.

Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is one of the leading causes of cancer-related mortality worldwide. Succinylation has been implicated in the pathogenesis of NSCLC at the molecular level. The succinyltransferase lysine acetyltransferase 2 A (KAT2A) exhibits oncogenic properties in diverse cancers; however, its role in NSCLC development remains unclear. This study employed bioinformatics techniques, clinical specimens, and NSCLC cell lines to analyze KAT2A expression. Cell malignancy was assessed using the cell counting kit-8 (CCK-8) and colony-formation assays. Glycolytic activity was evaluated by measuring glucose uptake, lactate production, extracellular acidification rate, and oxygen consumption rate. The underlying mechanisms were explored using quantitative real-time polymerase chain reaction, immunoblotting, immunoprecipitation, immunofluorescence, and cycloheximide chase assays. The results showed that KAT2A expression was notably higher in NSCLC and was linked to poor prognosis. Knockdown of KAT2A suppressed NSCLC cell growth and glycolysis. Mechanistically, KAT2A knockdown reduced the succinylation of transforming growth factor beta receptor 2 (TGFβR2) at lysine 493, leading to decreased expression of TGFβR2. A mutation at this site attenuated the oncogenic and glycolytic effects induced by TGFβR2 overexpression. Moreover, in vivo experiments demonstrated that KAT2A knockdown markedly inhibited tumor growth. Our findings suggest that KAT2A functions as an oncogenic driver in NSCLC by modulating the succinylation of TGFβR2, underscoring its potential as a therapeutic target.