SOX10 Regulates Melanoma Metastasis Through the IRF1-ITGA3/EphA2-FAK Pathway

Melanoma heterogeneity contributes to increased metastatic potential. Although a subpopulation characterized by MITF^low/AXL^high has been linked to invasiveness, the underlying mechanisms remain unclear. In this study, we identified cell migration-related gene sets as significantly enriched after the knockdown of SOX10 in melanoma. Both in silico analysis and in vitro analysis identified ITGA3 and EPHA2 as downstream effectors of SOX10-mediated migration, essential for cell adhesion and random motility, respectively. Moreover, the oncogenic activation of MAPK was necessary for increased random motility through EphA2 phosphorylation at the Ser 897 residue. We also identified IRF1 as an upstream regulator of both ITGA3 and EphA2 after the knockdown of SOX10. Notably, IRF1 suppression or the treatment with the FAK inhibitor, defactinib, significantly reduced melanoma metastasis in vivo. These findings demonstrate that the reduced expression of SOX10 promotes melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway and highlight FAK inhibition as a potential therapeutic strategy.