Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration.
Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration.
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Fbxw7alpha 通过泛素化介导的降解调节 SOX10 稳定性，从而调节黑色素瘤细胞迁移。
DOI：
10.18632/oncotarget.5639
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Ouyang N
中科院分区：
文献类型：
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作者：
Lv XB;Wu W;Tang X;Wu Y;Zhu Y;Liu Y;Cui X;Chu J;Hu P;Li J;Guo Q;Cai Z;Wu J;Hu K;Ouyang N
据报道，SOX 10的失调与多种癌症类型的进展相关，包括黑素细胞肿瘤和神经系统肿瘤。然而，SOX 10在这些肿瘤中失调的机制知之甚少。在这项研究中，我们报告SOX 10是Fbxw7α E3泛素连接酶的直接底物，Fbxw7α E3泛素连接酶是多种癌症的肿瘤抑制因子。Fbxw7α通过SOX 10的CPD结构域促进SOX 10泛素化介导的转换此外，GSK 3 β在CPD结构域磷酸化SOX 10，并促进Fbxw7α介导的SOX 10降解。此外，在黑色素瘤细胞中，SOX 10蛋白水平与Fbxw7α呈负相关，Fbxw7α水平的调节可调节SOX 10及其下游基因MIA的表达。更重要的是，SOX 10逆转了Fbxw7α介导的对黑色素瘤细胞迁移的抑制。这项研究提供了证据表明，肿瘤抑制因子Fbxw7α是负责降解SOX 10的E3泛素连接酶，并表明Fbxw7α的减少可能有助于黑素瘤细胞中SOX 10的上调。
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.