title: USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.
abstract: Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology, Urology, Radiation Oncology, Pathology, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Comprehensive Cancer Center; Department of Pathology, Johns Hopkins University, Baltimore, Maryland; and Institute of Biomedical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Schrecengost
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Goodwin
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schiewer
authors.forename: Mark W
authors.initials: MW
authors.lastname: Urban
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stanek
authors.forename: Robyn T
authors.initials: RT
authors.lastname: Sussman
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Hicks
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Birbe
authors.forename: Rossitza A
authors.initials: RA
authors.lastname: Draganova-Tacheva
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Angelo M
authors.initials: AM
authors.lastname: DeMarzo
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase
chemical_list: D059002:Androgen Receptor Antagonists; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human; D046988:Proteasome Endopeptidase Complex