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

MdmX is a substrate for the deubiquitinating enzyme USP2a

“…2 was purchased from Dharmacon, Lafayette, CO, USA. The siRNA USP2a (1) is identical to that previously described (Priolo et al, 2006;Stevenson et al, 2007) and siRNA USP2a (2) targets the following sequence: CUCG UCCAUACUCCAAGAA.…”

“…USP2a is overexpressed in prostate cancer (Graner et al, 2004). This is associated with a reduction in p53 target gene expression, suggesting that USP2a overexpression could contribute to tumourigenesis by repression of p53 (Priolo et al, 2006).…”

“…We have previously shown that USP2a can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination (Stevenson et al, 2007). USP2a has oncogenic properties and its overexpression can prevent apoptosis induced by chemotherapeutic agents (Graner et al, 2004;Priolo et al, 2006). USP2a knockdown results in increased p53 protein expression and upregulation of p53 target genes (Priolo et al, 2006;Stevenson et al, 2007).…”

“…USP2a has oncogenic properties and its overexpression can prevent apoptosis induced by chemotherapeutic agents (Graner et al, 2004;Priolo et al, 2006). USP2a knockdown results in increased p53 protein expression and upregulation of p53 target genes (Priolo et al, 2006;Stevenson et al, 2007). USP2a mRNA is expressed in a range of normal tissues, the highest level of expression being in the testis (Lin et al, 2001;Park et al, 2002;Gousseva and Baker, 2003).…”

Deubiquitinases in cancer: new functions and therapeutic options

“…Furthermore, USP1 expression correlates with initial steps of transformation in gastric cancer (Luise et al, 2011), whereas USP2 is overexpressed in ovarian and prostate carcinomas and is associated with lesions of poor prognosis . Moreover, overexpression of USP2 protects prostate cancer cells from apoptosis and confers them resistance to chemotherapeutic agents by reducing p53 stability (Priolo et al, 2006). Conversely, USP2 expression is downregulated in breast carcinomas, suggesting that this DUB may have pro-or antitumor properties that are exerted in a time-and tissue-specific manner (Metzig et al, 2011).…”