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The Isopeptidase USP2a Protects Human Prostate Cancer from Apoptosis

¹ Medical Oncology, Dana-Farber Cancer Institute and ² Pathology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ³ Novartis Pharma, Oncology Research, Basel, Switzerland; ⁴ Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina; and ⁵ Departments of Medical Oncology and Experimental Oncology, Regina Elena Cancer Institute, ⁶ INeMM, National Research Council and ⁷ Endocrinology, Catholic University, Rome, Italy

Requests for reprints: Massimo Loda, Dana-Farber Cancer Institute, D1536, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4001; Fax: 617-632-4005; E-mail: massimo_loda{at}dfci.harvard.edu.

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. (Cancer Res 2006; 66(17): 8625-32)