title: The isopeptidase USP2a protects human prostate cancer from apoptosis.
abstract: Deubiquitinating enzymes can prevent the destruction of protein substrates prior to proteasomal degradation. The ubiquitin-specific protease 2a (USP2a) deubiquitinates the antiapoptotic proteins Fatty Acid Synthase and Mdm2. Here, we show that when USP2a is overexpressed in nontransformed cells, it exhibits oncogenic behavior both in vitro and in vivo and prevents apoptosis induced by chemotherapeutic agents. Notably, USP2a silencing in several human cancer cell lines results in apoptosis. Gene set enrichment analysis, which focuses on groups of genes sharing biological function or regulatory pathways, was done on microarray expression data from human prostate cancers. The cell death-related gene set, as well as a selected cluster of validated p53 target genes, were significantly enriched in the low USP2a expression group of tumors. Conversely, genes implicated in fatty acid metabolism were significantly associated with tumors expressing high USP2a (44%). The expression profile analysis is consistent with the effects of USP2a on its known targets, i.e., Fatty Acid Synthase and Mdm2, defining a subset of prostate tumors resistant to apoptosis. USP2a thus represents a therapeutic target in prostate cancer.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Priolo
authors.forename: Dan
authors.initials: D
authors.lastname: Tang
authors.forename: Mohan
authors.initials: M
authors.lastname: Brahamandan
authors.forename: Barbara
authors.initials: B
authors.lastname: Benassi
authors.forename: Ewa
authors.initials: E
authors.lastname: Sicinska
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Porrello
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Johann
authors.initials: J
authors.lastname: Zimmermann
authors.forename: Phillip
authors.initials: P
authors.lastname: Febbo
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D019759:Carbon-Nitrogen Lyases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase
chemical_list: D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D025801:Ubiquitin; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase