Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
Xi'an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
Cell Death Dis. 2022 Sep 9;13(9):778. doi: 10.1038/s41419-022-05128-6.
The mechanistic (formally "mammalian") target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer. In our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of sestrin2, which is an inhibitor of the mTOR signaling pathway. Together, we provide novel insights into the pathogenesis of bladder cancer and first prove that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis, which may be exploited in the future for the diagnosis and treatment of this malignancy.
雷帕霉素靶蛋白（mTOR）途径的机制（形式上称为“哺乳动物”）作为细胞生长和癌症进展等各种生物过程的关键调节剂。在膀胱癌中，最近的发现表明 mTOR 复合物 1 具有促进癌症的作用，引起了广泛的关注。然而，mTOR 信号在膀胱癌中的调节很复杂，其潜在机制尚不清楚。在这里，我们报告去泛素化酶卵巢肿瘤结构域蛋白 5（OTUD5）可以激活 mTOR 信号通路，促进癌症进展，并在膀胱癌中表现出其致癌潜力。在我们的研究中，我们发现 OTUD5 去泛素化了一种 RING 型 E3 连接酶，RNF186，并稳定了其功能。此外，RNF186 的稳定进一步导致 sestrin2 的降解， sestrin2 是 mTOR 信号通路的抑制剂。总之，我们为膀胱癌的发病机制提供了新的见解，并首次证明 OTUD5 可以通过 OTUD5-RNF186-sestrin2-mTOR 轴促进膀胱癌的进展，这可能在未来用于这种恶性肿瘤的诊断和治疗。
