Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial-Mesenchymal Transition via Stabilizing Snail

Epithelial-mesenchymal transition (EMT) represents one of the most important events in the invasion of glioblastomas (GBM); therefore, better understanding of mechanisms that govern EMT is crucial for the treatment of GBMs. In this study, we report that the deubiquitinase ubiquitin-specific protease 3 (USP3) is significantly upregulated in GBMs and correlates with a shorter median overall and relapse-free survival. Silencing of USP3 attenuates the migration and invasion abilities of GBM cells in vitro and tumor growth in an orthotopic xenograft mouse model. Mechanistically, we identify USP3 as a bona fide deubiquitinase for Snail, a master transcription factor that promotes EMT, in GBM cells. USP3 interacts directly with Snail and stabilizes Snail via deubiquitination. Ectopic expression of Snail could largely rescue the inhibitory effects of USP3 depletion on migration, invasion, and tumor growth of GBM cells. In addition, we found that USP3 strongly correlates with Snail expression in primary human GBM samples. Overall, our findings reveal a critical USP3-Snail signaling axis in EMT and invasion, and provide an effective therapeutic approach against GBM.

上皮 - 间质转化（EMT）是胶质母细胞瘤（GBM）侵袭过程中最重要的事件之一；因此，更好地理解调控EMT的机制对于GBM的治疗至关重要。在本研究中，我们报道去泛素化酶泛素特异性蛋白酶3（USP3）在GBM中显著上调，并与较短的中位总生存期和无复发生存期相关。沉默USP3可减弱GBM细胞在体外的迁移和侵袭能力以及在原位异种移植小鼠模型中的肿瘤生长。从机制上讲，我们确定在GBM细胞中，USP3是Snail（一种促进EMT的主要转录因子）的真正去泛素化酶。USP3与Snail直接相互作用，并通过去泛素化稳定Snail。Snail的异位表达可在很大程度上挽救USP3缺失对GBM细胞迁移、侵袭和肿瘤生长的抑制作用。此外，我们发现USP3与原发性人类GBM样本中的Snail表达密切相关。总体而言，我们的研究结果揭示了EMT和侵袭过程中一个关键的USP3 - Snail信号轴，并为针对GBM的治疗提供了一种有效的方法。