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

Abstract

// Xiao-Bin Lv 1, 2, * , Wei Wu 2, 4, * , Xiaofeng Tang 1, * , Yanqing Wu 4 , Yinghua Zhu 2 , Yujie Liu 2, 4 , Xiuying Cui 2 , Junjun Chu 2, 4 , Pengnan Hu 2, 4 , Jingjing Li 2, 4 , Qiannan Guo 2, 4 , Zeming Cai 1 , Juan Wu 5 , Kaishun Hu 2 , Nengyong Ouyang 2, 3 1 Nanchang Key Laboratory of Cancer Pathogenesis and Translational Research, the Third Affiliated Hospital, Nanchang University, Nanchang, China 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 3 Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 4 Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 5 Cancer Center of Guangzhou Medical University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Xiao-Bin Lv, e-mail: promab2006@126.com Nengyong Ouyang, e-mail: ouyangny@sina.com Keywords: SOX10, Fbxw7α, ubiquitination, melanoma, GSK3β Received: April 27, 2015      Accepted: September 29, 2015      Published: October 09, 2015 ABSTRACT 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 Fbxw7α E3 ubiquitin ligase, a tumor suppressor in multiple cancers. Fbxw7α promotes SOX10 ubiquitination-mediated turnover through CPD domain of SOX10. Besides, GSK3β phosphorylates SOX10 at CPD domain and facilitates Fbxw7α-mediated SOX10 degradation. Moreover, SOX10 protein levels were inversely correlated with Fbxw7α in melanoma cells, and modulation of Fbxw7α levels regulated the expression of SOX10 and its downstream gene MIA. More importantly, SOX10 reversed Fbxw7α-mediated suppression of melanoma cell migration. This study provides evidence that the tumor suppressor Fbxw7α is the E3 ubiquitin ligase responsible for the degradation of SOX10, and suggests that reduced Fbxw7α might contribute to the upregulation of SOX10 in melanoma cells.