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....

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Bibliographic Details
Published in:Cell death & disease 2022-09, Vol.13 (9), p.778-778, Article 778
Main Authors: Hou, Tao, Dan, Weichao, Liu, Tianjie, Liu, Bo, Wei, Yi, Yue, Chenyang, Que, Taotao, Ma, Bohan, Lei, Yuzeshi, Wang, Zixi, Zeng, Jin, Fan, Yizeng, Li, Lei
Format: Article
Language:English
Subjects:
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Antibodies
Biochemistry
Biomedical and Life Sciences
Bladder cancer
Cancer
Cell Biology
Cell Culture
Deubiquitinating Enzymes - genetics
Endopeptidases - metabolism
Female
Human papillomavirus
Humans
Immunology
Life Sciences
Malignancy
Mechanistic Target of Rapamycin Complex 1 - metabolism
Neoplasm Proteins
Rapamycin
Signal Transduction
TOR protein
TOR Serine-Threonine Kinases - genetics
Tumors
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Urinary Bladder Neoplasms - genetics
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-022-05128-6