The mechanism by which KAT2A increases the stability of CDC25A through acetylation to regulate glycolysis and mediate lung adenocarcinoma immune escape.

BACKGROUND: Immune escape is a defining feature of malignant tumor initiation and progression. CDC25A is an oncogenic gene, highly expressed in various cancers, yet the molecular mechanisms behind its upregulation in lung adenocarcinoma (LUAD) and its role in immune evasion remain incompletely understood. METHODS: We assessed CDC25A and lysine acetyltransferase 2 A (KAT2A) expression in LUAD patients, leveraging the TCGA-LUAD database, and verified their mRNA and protein levels in LUAD cell lines and tissues with qRT-PCR and WB. Kaplan-Meier analysis was used to explore the prognostic relevance of CDC25A expression in LUAD, while Pearson correlation was performed to analyze the relationship between CDC25A and KAT2A. Cell viability and proliferation were determined using CCK-8 and colony formation assays. A cell metabolic analyzer was used to assess metabolic rates (ECAR and OCR). Glucose and lactate levels in the supernatant were measured using respective assay kits. CD8(+)T cells were co-cultured with LUAD cells, with their activation monitored by flow cytometry. The killing capacity of CD8(+)T cells towards LUAD cells was evaluated with lactate dehydrogenase (LDH) and ELISA kits. The interaction between CDC25A and hexokinase 2 (HK2) and their cytoplasmic co-localization were confirmed by CO-immunoprecipitation (CO-IP) and immunofluorescence. Chromatin Immunoprecipitation (ChIP) verified the binding relationship between KAT2A and CDC25A. In vivo validation was conducted in a mouse allograft tumor model. RESULTS: CDC25A was upregulated in LUAD tissues and cells, with an identified link to poorer patient survival. Knocking down CDC25A expression hindered LUAD cell activation and proliferation, lowered aerobic glycolysis, elevated the ratio of CD8(+)IFN-γ(+) T cells, and boosted the cytotoxicity of CD8(+)T cells against tumor cells. Moreover, CDC25A could interact with HK2 to impact its protein expression, thereby modulating aerobic glycolysis in LUAD cells. KAT2A, highly expressed in LUAD tissues and cells, was positively correlated with CDC25A levels. KAT2A promoted the acetylation of CDC25A, promoting immune evasion in LUAD cells. The in vivo and in vitro studies had similar results. CONCLUSION: This research reveals that KAT2A promotes the expression of CDC25A via acetylation. Subsequently, CDC25A interacts with HK2 to control aerobic glycolysis, thereby driving the immune evasion process in LUAD. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03544-2.