Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, Tomtebodavägen 16, 171 65, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, Tomtebodavägen 16, 171 65, Stockholm, Sweden.
Biochem Biophys Res Commun. 2018 Aug 25;502(4):429-434. doi: 10.1016/j.bbrc.2018.05.156. Epub 2018 Jun 1.
Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism governing the switch of cells from an epithelial to a motile mesenchymal-like state. This transdifferentiation is regulated by key transcription factors, including Slug. The stability and function of Slug can be regulated by multiple mechanisms, including ubiquitin-mediated post-translational modifications. Here, by using a genome wide siRNA screen for human deubiquitinating enzymes (DUBs), we identified USP10 as a deubiquitinase for Slug in cancer cells. USP10 interacts with Slug and mediates its degradation by the proteasome. Importantly, USP10 is concomitantly highly expressed with Slug in cancer biopsies. Genetic knockdown of USP10 leads to suppressed Slug levels with a decreased expression of the mesenchymal marker Vimentin. Further, it reduces the migratory capacity of cancer cells. Reversely, overexpression of USP10 elevates the level of both Slug and Vimentin. Our study identifies USP10 as a regulator of the EMT-transcription factor Slug and cell migration.
上皮-间充质转化（EMT）是一种基本的机制，控制着细胞从上皮状态向运动性间充质样状态的转变。这种转分化受关键转录因子的调节，包括 Slug。Slug 的稳定性和功能可以通过多种机制进行调节，包括泛素介导的翻译后修饰。在这里，我们通过使用全基因组 siRNA 筛选人类去泛素化酶（DUBs），鉴定 USP10 是癌细胞中 Slug 的去泛素酶。USP10 与 Slug 相互作用，并通过蛋白酶体介导其降解。重要的是，USP10 与 Slug 在癌症活检组织中同时高度表达。USP10 的遗传敲低导致 Slug 水平降低，间充质标志物波形蛋白的表达减少。此外，它还降低了癌细胞的迁移能力。相反，USP10 的过表达会提高 Slug 和波形蛋白的水平。我们的研究确定 USP10 是 EMT 转录因子 Slug 和细胞迁移的调节因子。
