Context: H3^K18ac is linked to gene expression and DNA damage. Nevertheless, whether H3^K18ac participates in regulating Ras-ERK1/2-affected lung cancer cell phenotypes remains unclear. Objective: We explored the effects of H3^K18ac on Ras-ERK1/2-affected lung cancer cell phenotypes. Material and methods: NCI-H2126 cells were transfected with, pEGFP-K-Ras^WT and pEGFP-K-Ras^G12V/T35S plasmids for 48 h, and transfection with pEGFP-N1 served as a blank control. Then H3^K18ac and AKT and ERK1/2 pathways-associated factors were examined. Different amounts of the H3^K18Q (0.5, 1, and 2 μg) plasmids and Ras^G12V/T35S were co-transfected into NCI-H2126 cells, cell viability, cell colonies and migration were analyzed for exploring the biological functions of H3^K18ac in NCI-H2126 cells. The ERK1/2 pathway downstream factors were detected by RT-PCR and ChIP assays. The regulatory functions of SIRT7, GCN5 and MDM2 in Ras-ERK1/2-regulated H3^K18ac expression were finally uncovered. Results: Ras^G12V/T35S transfection decreased the expression of H3^K18ac about 2.5 times compared with the pEGFP-N1 transfection group, and activated ERK1/2 and AKT pathways. Moreover, H3^K18ac reduced cell viability, colonies, migration, and altered ERK1/2 downstream transcription in NCI-H2126 cells. Additionally, SIRT7 knockdown increased H3^K18ac expression and repressed cell viability, migration and the percentage of cells in S phase by about 50% compared to the control group, as well as changed ERK1/2 downstream factor expression. Besides, Ras-ERK1/2 decreased H3^K18ac was linked to MDM2-regulated GCN5 degradation. Conclusion: These observations disclosed that Ras-ERK1/2 promoted the development of lung cancer via decreasing H3^K18ac through MDM2-mediated GCN5 degradation. These findings might provide a new therapeutic strategy for lung cancer.

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