Deubiquitinase OTUD5 modulates mTORC1 signaling to promote bladder cancer progression

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.

Automated summary

This study reveals that the deubiquitinating enzyme OTUD5 activates the mTOR signaling pathway to promote bladder cancer progression. OTUD5 stabilizes the function of RNF186, a RING-type E3 ligase, leading to the degradation of sestrin2, an inhibitor of the mTOR signaling pathway.