CD82 suppresses CD44 alternative splicing-dependent melanoma metastasis by mediating U2AF2 ubiquitination and degradation.
CD82 suppresses CD44 alternative splicing-dependent melanoma metastasis by mediating U2AF2 ubiquitination and degradation.
复制标题
CD82 通过介导 U2AF2 泛素化和降解来抑制 CD44 选择性剪接依赖性黑色素瘤转移
作者：
Zhang P;Feng S;Liu G;Wang H;Fu A;Zhu H;Ren Q;Wang B;Xu X;Bai H;Dong C
黑色素瘤是最致命的皮肤癌之一，因为它的早期转移扩散。CD 44（CD 44 v）是一种细胞表面糖蛋白，在转移性黑色素瘤中高度表达。迄今为止，对黑色素瘤中CD 44选择性剪接的调节机制及其致病作用知之甚少。在这里，我们研究了CD 44的表达水平在一个大的黑素细胞病变在不同阶段。我们发现，CD 44 v8 -10和剪接因子U2 AF 2的表达在黑色素瘤进展过程中显著增加，而CD 82/KAI 1（肿瘤抑制因子的四跨膜蛋白家族）在转移性黑色素瘤中减少。与CD 82水平呈负相关的CD 44 v8 -10和U2 AF 2表达水平在原发性黑素瘤中显著高于发育不良痣，并在转移性黑素瘤中进一步升高。我们还发现，CD 44 v8 -10和U2 AF 2表达水平较高的患者往往生存期较短。通过使用体内和体外测定，我们证明了CD 82抑制黑素瘤上CD 44 v8 -10的产生。在机制上，U2 AF 2是CD 82的下游靶标，并且在恶性黑色素瘤中促进CD 44 v8 -10选择性剪接。U2 AF 2介导的CD 44亚型转换是体外黑色素瘤迁移和体内肺和肝转移所必需的。值得注意的是，CD 82的过表达通过诱导U2 AF 2泛素化来抑制U2 AF 2活性。此外，我们的数据表明，增强黑色素瘤迁移的U2 AF 2依赖性CD 44 v8 -10剪接介导的Src/黏着斑激酶/RhoA激活和应力纤维的形成，以及CD 44-E-选择素结合增强。这些发现揭示了CD 82在切断U2 AF 2介导的CD 44选择性剪接与癌症侵袭性之间的联系方面迄今未被认识的功能，在黑色素瘤中具有潜在的预后和治疗意义。
Melanoma is one of the most lethal forms of skin cancer because of its early metastatic spread. The variant form of CD44 (CD44v), a cell surface glycoprotein, is highly expressed on metastatic melanoma. The mechanisms of regulation of CD44 alternative splicing in melanoma and its pathogenic contributions are so far poorly understood. Here, we investigated the expression level of CD44 in a large set of melanocytic lesions at different stages. We found that the expression of CD44v8–10 and a splicing factor, U2AF2, is significantly increased during melanoma progression, whereas CD82/KAI1, a tetraspanin family of tumor suppressor, is reduced in metastatic melanoma. CD44v8–10 and U2AF2 expression levels, which are negatively correlated with CD82 levels, are markedly elevated in primary melanoma compared with dysplastic nevi and further increased in metastatic melanoma. We also showed that patients with higher CD44v8–10 and U2AF2 expression levels tended to have shorter survival. By using both in vivo and in vitro assays, we demonstrated that CD82 inhibits the production of CD44v8–10 on melanoma. Mechanistically, U2AF2 is a downstream target of CD82 and in malignant melanoma facilitates CD44v8–10 alternative splicing. U2AF2-mediated CD44 isoform switch is required for melanoma migration in vitro and lung and liver metastasis in vivo. Notably, overexpression of CD82 suppresses U2AF2 activity by inducing U2AF2 ubiquitination. In addition, our data suggested that enhancement of melanoma migration by U2AF2-dependent CD44v8–10 splicing is mediated by Src/focal adhesion kinase/RhoA activation and formation of stress fibers, as well as CD44-E-selectin binding reinforcement. These findings uncovered a hitherto unappreciated function of CD82 in severing the linkage between U2AF2-mediated CD44 alternative splicing and cancer aggressiveness, with potential prognostic and therapeutic implications in melanoma.