title: Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer.
abstract: The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor-mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Anupama
authors.initials: A
authors.lastname: Pal
authors.affiliation: Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Young
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan. ndonato@med.umich.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
mesh_terms: D000818:Animals; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011480:Protease Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D011480:Protease Inhibitors; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex