S-adenosylmethionine enhances anti-PD-1 efficacy in uveal melanoma by targeting EZH2.

OBJECTIVE: To investigate the effect of S-adenosylmethionine (SAM) on enhancing anti-programmed death 1 (PD-1) therapy in uveal melanoma (UM) by targeting Enhancer of Zeste homolog 2 (EZH2). The synergistic effect of SAM in combination with the PD-1 inhibitor Pembrolizumab was verified by screening its target of action, assessing its effect on cell viability, proliferation, migration, and apoptosis. METHODS: We used network pharmacology combined with transcriptomics data, then combined GEOquery tool and PharmMapper database to select the targets of SAM in treating UM, and performed differential gene expression analysis using the limma algorithm package. Multidimensional clustering heatmap and functional enrichment analysis were performed using the ComplexHeatmap and clusterProfiler tools to analyze the mechanism of SAM in targeting key targets in UM. In addition, we developed a SAM targeted accurate prognostic prediction system for UM by integrating multi-omics data and applying machine learning algorithms. Finally, to validate the effects of SAM targeting key targets of UM, we examined the effects of SAM and its combination with Pembrolizumab on UM cell viability, proliferation, migration, and apoptosis using CCK-8, transwell migration assay, and flow cytometry. RESULTS: The expression of EZH2 was significantly higher in various cancer types than in normal tissues (P < 0.05), and its high expression was closely related to the infiltration pattern of specific types of immune cells. Further Kaplan-Meier survival analysis showed that high EZH2 expression was associated with worse patient outcomes, particularly for CD8 + T cells, NK cell-related immune outcomes. However, SAM significantly inhibited the proliferation of MUM-2B and C-918 cell lines with IC50 values of 224.4 µmol/L and 220.9 µmol/L, respectively, and down-regulated the mRNA expression levels of key genes EZH2 and CD279. Finally, SAM showed synergistic effects when combined with Pembrolizumab, significantly enhanced the inhibitory effect on EZH2, and effectively inhibited cell proliferation, migration, and promoted apoptosis. CONCLUSION: As a potential anticancer drug, SAM can not only significantly inhibit the proliferation and migration of UM cells, but also promote apoptosis. In particular, SAM showed a stronger antitumor effect when it was combined with Pembrolizumab, providing a theoretical basis for the development of new strategies based on EZH2-targeted therapy and suggesting the potential of this combination therapy in clinical application.