title: An atlas of altered expression of deubiquitinating enzymes in human cancer.
abstract: BACKGROUND
  Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin (Ub) or ubiquitin-like gene products, remodel polyubiquitin(-like) chains on target proteins, and counteract protein ubiquitination exerted by E3 ubiquitin-ligases. A wealth of studies has established the relevance of DUBs to the control of physiological processes whose subversion is known to cause cellular transformation, including cell cycle progression, DNA repair, endocytosis and signal transduction. Altered expression of DUBs might, therefore, subvert both the proteolytic and signaling functions of the Ub system.
  
  
  RESULTS
  In this study, we report the first comprehensive screening of DUB dysregulation in human cancers by in situ hybridization on tissue microarrays (ISH-TMA). ISH-TMA has proven to be a reliable methodology to conduct this kind of study, particularly because it allows the precise identification of the cellular origin of the signals. Thus, signals associated with the tumor component can be distinguished from those associated with the tumor microenvironment. Specimens derived from various normal and malignant tumor tissues were analyzed, and the "normal" samples were derived, whenever possible, from the same patients from whom tumors were obtained. Of the ∼90 DUBs encoded by the human genome, 33 were found to be expressed in at least one of the analyzed tissues, of which 22 were altered in cancers. Selected DUBs were subjected to further validation, by analyzing their expression in large cohorts of tumor samples. This analysis unveiled significant correlations between DUB expression and relevant clinical and pathological parameters, which were in some cases indicative of aggressive disease.
  
  
  CONCLUSIONS
  The results presented here demonstrate that DUB dysregulation is a frequent event in cancer, and have implications for therapeutic approaches based on DUB inhibition.
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Luise
authors.forename: Maria
authors.initials: M
authors.lastname: Capra
authors.forename: Maddalena
authors.initials: M
authors.lastname: Donzelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Jodice
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
mesh_terms: D010450:Endopeptidases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment
chemical_list: D017874:Immediate-Early Proteins; D010450:Endopeptidases