MYST2 histone acetyltransferase promotes lung adenocarcinoma progression by regulating the p38 MAPK signaling pathway

•MYST2 histone acetyltransferase promotes tumorigenesis of LUAD.•High expression of MYST2 is negatively correlated with lung cancer survival.•MYST2 interacts with MEK6 and promotes the phosphorylation of p38 via directly influencing the interaction between MEK6 and p38. Lung cancer, particularly lung adenocarcinoma, poses a significant health challenge due to its high incidence and mortality rates. Despite advancements in targeted therapies, treatment outcomes for lung adenocarcinoma remain unsatisfactory. This study explores the role of the histone acetyltransferase MYST2 in lung adenocarcinoma and its potential as a therapeutic target. An analysis using the TIMER 2.0 and TCGA databases was performed to compare the expression levels of MYST2 between lung adenocarcinoma tissues and normal tissues. Functional assays, including cell proliferation, migration, and invasion, were conducted to evaluate the effects of MYST2 overexpression and knockout in lung cancer cells. Co-immunoprecipitation and GST pull-down assays were utilized to identify interactions involving the MYST domain of MYST2 and p38, while also assessing the impact of MYST2 on the binding between MEK6 and p38. The analysis revealed that MYST2 was significantly up-regulated in lung adenocarcinoma tissues compared to normal tissues and was associated with poor prognosis. Functional assays demonstrated that MYST2 overexpression promoted, whereas MYST2 knockout inhibited, lung cancer cell proliferation, migration, and invasion. Mechanistically, MYST2 enhanced the phosphorylation of p38 and ERK. Co-immunoprecipitation and GST pull-down assays identified the MYST domain of MYST2 as crucial for its interaction with p38. Additionally, MYST2 overexpression facilitated the binding of MEK6 to p38, indirectly influencing p38 activity. These findings suggest that MYST2 acts as an oncogene in lung cancer by modulating p38 phosphorylation through the MYST domain, underscoring its potential as a prognostic marker and therapeutic target.