Ubiquitin-specific-processing proteases (USPs), the largest deubiquitinating enzyme (DUB) subfamily, play critical roles in cancer. However, clinical utility of USPs is hindered by limited knowledge about their varied and substrate-dependent actions. Here, we performed a comprehensive investigation on pan-cancer impacts of USPs by integrating multi-omics data and annotated data resources, especially a deubiquitination network. Meaningful insights into the roles of 54 USPs in 29 types of cancers were generated. Although rare mutations were observed, a majority of USPs exhibited significant expressional alterations, prognostic impacts and strong correlations with cancer hallmark pathways. Notably, from our DUB-substrate interaction prediction model, additional USP-substrate interactions (USIs) were recognized to complement knowledge gap about cancer-relevant USIs. Intriguingly, expression signatures of the USIs revealed clinically meaningful cancer subtypes, where key USPs and substrates cooperatively contributed to significant prognosis differences among subtypes. Overall, this investigation provides a valuable resource to assist mechanism research and clinical utility about USPs.
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Dedicated to the 70th anniversary of Dalian Institute of Chemical Physics, CAS. We thank Guowang Xu, Tongming Li, and all members of the Dr. Piao laboratory for helpful discussions and suggestions. This study is supported by the National Natural Science Foundation of China (Grant Nos. 81672440, 31701156, 81502024, and 81572881), Project funded by China Postdoctoral Science Foundation (No. 2017M611281), Innovation program of science and research from the DICP, CAS (DICP TMSR201601, DICP ZZBS201803).
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Chen, D., Ning, Z., Chen, H. et al. An integrative pan-cancer analysis of biological and clinical impacts underlying ubiquitin-specific-processing proteases. Oncogene 39, 587–602 (2020). https://doi.org/10.1038/s41388-019-1002-4