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.

泛素结合酶E2S（UBE2S）是泛素化过程中重要的E2酶，在多种恶性肿瘤中表现出致癌活性。然而，尚不清楚 UBE2S 是否在膀胱癌 (UBC) 的发展中起作用。在目前的研究中，我们的数据证实了 UBC 中的 UBE2S 上调。体外和体内实验表明，UBE2S 敲低导致增殖减弱和细胞凋亡增强，这与 UBE2S 过表达的表型相反。功能获得和丧失分析证实 UBE2S 通过介导哺乳动物雷帕霉素复合物 1 (mTORC1) 通路的激活而在 UBC 中发挥致癌活性。此外，我们发现这种 UBE2S 调节的致癌机制是直接靶向结节性硬化症 1 (TSC1) 的结果，TSC1 是 mTOR 信号传导的上游抑制剂，用于普遍降解。综上所述，本研究表明 UBE2S 是 UBC 中的致癌物，并通过普遍降解 TSC1 促进 UBC 进展。因此，这介导了 mTOR 通路的激活，