Proteomic Analysis of the E3 Ubiquitin-Ligase Hakai Highlights a Role in Plasticity of the Cytoskeleton Dynamics and in the Proteasome System
Proteomic Analysis of the E3 Ubiquitin-Ligase Hakai Highlights a Role in Plasticity of the Cytoskeleton Dynamics and in the Proteasome System
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DOI：
10.1021/acs.jproteome.7b00046
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发表时间：
2017-08-01
影响因子：
4.4
通讯作者：
Figueroa, Angelica
中科院分区：
文献类型：
--
作者：
Diaz-Diaz, Andrea;Casas-Pais, Alba;Figueroa, Angelica
癌是最常见的癌症类型，起源于上皮细胞。从腺瘤到癌的转变与E-钙粘蛋白的丢失有关，因此，细胞接触中断。E-钙粘蛋白是一种肿瘤抑制因子，它在上皮-间质转化（EMT）过程中下调;事实上，它的缺失是预后不良的预测因子。Hakai是一种E3遍在蛋白连接酶蛋白，介导E-钙粘蛋白遍在化、内吞并最终降解，导致细胞接触的改变。虽然E-钙粘蛋白是Hakai活性最确定的底物，但Hakai的其他调节分子靶点可能参与肿瘤进展期间的癌细胞可塑性。在这项工作中，我们采用iTRAQ方法来探索Hakai在肿瘤进展过程中驱动EMT的新分子途径，我们的结果表明，Hakai可能对细胞外泌体相关蛋白，细胞外外泌体相关蛋白，RNA相关蛋白和代谢相关蛋白产生重要影响。此外，在Hakai驱动的EMT过程中，几种蛋白酶体亚基的表达显著降低。由于蛋白酶体抑制剂越来越多地用于癌症治疗，我们的研究结果表明，E3泛素连接酶，如Hakai，可能是一个更好的目标比蛋白酶体使用新的特异性抑制剂在肿瘤亚型以下EMT。
Carcinoma, the most common type of cancer, arises from epithelial cells. The transition from adenoma to carcinoma is associated with the loss of E-cadherin and, in consequence, the disruption of cell cell contacts. E-cadherin is a tumor suppressor, and it is down-regulated during epithelial-to-mesenchymal transition (EMT); indeed, its loss is a predictor of poor prognosis. Hakai is an E3 ubiquitin-ligase protein that mediates E-cadherin ubiquitination, endocytosis and finally degradation, leading the alterations of cell cell contacts. Although E-cadherin is the most established substrate for Hakai activity, other regulated molecular targets for Hakai may be involved in cancer cell plasticity during tumor progression. In this work we employed an iTRAQ approach to explore novel molecular pathways involved in Hakai-driven EMT during tumor progression, Our results show that Hakai may have an important influence on cytoskeleton-related proteins, extracellular exosome-associated proteins, RNA-related proteins and proteins involved in metabolism. Moreover, a profound decreased expression in several proteasome subunits during Hakai-driven EMT was highlighted. Since proteasome inhibitors are becoming increasingly used in cancer treatment, our findings suggest that the E3 ubiquitin-ligase, such as Hakai, may be a better target than proteasome for using novel specific inhibitors in tumor subtypes that follow EMT.