SOX10 regulates melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway.

Melanoma heterogeneity is associated with an enhanced metastatic potential. Although an invasive state with MITFlow/AXLhigh in the melanoma subpopulation has been identified using a single-cell RNA-seq analysis, the mechanisms by which these cells acquire their invasiveness remains unclear. In the present study, we identified the gene set related to cell migration as one of the enriched gene ontologies after the knockdown of SOX10 in melanoma. We demonstrated that the knockdown of SOX10 induced melanoma migration independent of MITF reduction or AXL induction. An in silico analysis and in vitro analysis revealed that ITGA3 and EphA2 were downstream molecules for SOX10-mediated migration, and were required for adhesive and random motile abilities, respectively. In addition, the oncogenic activation of MAPK was required for increased random motility through EphA2 phosphorylation at the Ser 897 residue. We also demonstrated the significance of IRF1 in the induction of both ITGA3 and EphA2 after the knockdown of SOX10. The FAK inhibitor, defactinib, suppressed metastasis in vivo. In summary, the present study showed that the reduced expression of SOX10 induced melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway and also suggests the potential of FAK inhibitors as candidate drugs for the treatment of melanoma metastasis.