Abstract
Background: Tumor migration in lung adenocarcinoma (LUAD) contributes to a poor prognosis by allowing malignant cells to escape the localized effects of radiotherapy, diminishing its overall efficacy. This study investigated the role of SET8, a methyltransferase, in LUAD migration and radiotherapy. Methods: In vitro experiments, including CRISPR/Cas9-mediated SET8 knockout, wound healing assays, and transwell migration assays, were used to assess the impact of SET8 on radiation-induced migration in LUAD cells. Bioinformatics analyses, such as differential expression analysis, clustering, functional enrichment, and CpG island methylation analysis, were performed using LUAD patient data from TCGA to examine the broader relationship between SET8, LUAD migration, and prognosis. Statistical methods, including Cox regression and LASSO regression, were employed to establish a prognostic model for radiotherapy outcomes, and drug sensitivity analysis was used to identify potential therapeutic agents. Results: Ionizing radiation induced migration in LUAD cells, coupled with altered SET8 expression. SET8 was found to engage in IR-induced migration through the PTTG1-PI3K-AKT signaling axis. Furthermore, elevated SET8 expression was more prevalent in LUAD patients with metastasis and correlated with adverse prognosis. Under equivalent X-ray irradiation doses, SET8 depletion significantly inhibited the migratory capability of LUAD cells. Finally, SET8-associated migration genes could predict the survival rate, radiation responsiveness, and drug sensitivity of radiotherapy patients. Conclusion: SET8 facilitates radiation-induced migration in LUAD through the PTTG1-PI3K-AKT pathway, and SET8-associated genes may act as valuable markers for predicting radiotherapeutic efficacy in LUAD patients.