Department of College of Clinical Medicine of Weifang Medical University, Weifang, China.
Department of Urology, The Affiliated Hospital of Weifang Medical University, Weifang, China.
Biochem Biophys Res Commun. 2021 Nov 12;578:7-14. doi: 10.1016/j.bbrc.2021.08.057. Epub 2021 Sep 6.
Ubiquitin-conjugating enzyme E2S (UBE2S), an important E2 enzyme in the process of ubiquitination, has exhibited oncogenic activities in various malignant tumors. However, it remains unknown whether UBE2S plays a role in urinary bladder cancer (UBC) development. In the current study, our data confirmed UBE2S upregulation in UBC. In vitro and in vivo experiments demonstrated that UBE2S knockdown resulted in attenuated proliferation and enhanced apoptosis, which was inverse to the phenotypes with UBE2S overexpression. Gain and loss of function assays confirmed that UBE2S exerts oncogenic activities in UBC by mediating the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we discovered that this UBE2S-modulated carcinogenic mechanism was in the consequence of directly targeting tuberous sclerosis 1 (TSC1), which is the upstream inhibitor of mTOR signaling for ubiquitous degradation. Taken together, this study demonstrated that UBE2S is a carcinogen in UBC and promotes UBC progression by ubiquitously degrading TSC1. This consequently mediates the activation of the mTOR pathway, suggesting a potential therapeutic regimen for UBC by targeting the newly identified UBE2S/TSC1/mTOR axis.
泛素连接酶 E2S（UBE2S）是泛素化过程中的一种重要 E2 酶，在各种恶性肿瘤中表现出致癌活性。然而，UBE2S 是否在膀胱癌（UBC）的发展中起作用尚不清楚。在本研究中，我们的数据证实了 UBE2S 在 UBC 中的上调。体外和体内实验表明，UBE2S 敲低导致增殖减弱和凋亡增强，这与 UBE2S 过表达的表型相反。获得和丧失功能实验证实，UBE2S 通过介导雷帕霉素靶蛋白复合物 1（mTORC1）通路的激活，在 UBC 中发挥致癌活性。此外，我们发现这种 UBE2S 调节的致癌机制是由于直接靶向哺乳动物雷帕霉素靶蛋白信号通路的上游抑制剂结节性硬化症 1（TSC1）而导致的。总之，这项研究表明 UBE2S 是 UBC 的致癌基因，并通过普遍降解 TSC1 促进 UBC 的进展。这继而介导了 mTOR 通路的激活，提示通过针对新鉴定的 UBE2S/TSC1/mTOR 轴，为 UBC 提供了一种潜在的治疗方案。
