Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration.

Dysregulation of SOX10 was reported to be correlated with the progression of multiple cancer types, including melanocytic tumors and tumors of the nervous system. However, the mechanisms by which SOX10 is dysregulated in these tumors are poorly understood. In this study, we report that SOX10 is a direct substrate of Fbxw7 alpha E3 ubiquitin ligase, a tumor suppressor in multiple cancers. Fbxw7a promotes SOX10 ubiquitination-mediated turnover through CPD domain of SOX10. Besides, GSK3 beta phosphorylates SOX10 at CPD domain and facilitates Fbxw7 alpha-mediated SOX10 degradation. Moreover, SOX10 protein levels were inversely correlated with Fbxw7 alpha a in melanoma cells, and modulation of Fbxw7 alpha levels regulated the expression of SOX10 and its downstream gene MIA. More importantly, SOX10 reversed Fbxw7 alpha-mediated suppression of melanoma cell migration. This study provides evidence that the tumor suppressor Fbxw7 alpha is the E3 ubiquitin ligase responsible for the degradation of SOX10, and suggests that reduced Fbxw7 alpha might contribute to the upregulation of SOX10 in melanoma cells.