The role of USP has been reported recently in

The role of USP11 has been reported recently in modulating a number of signaling cascades such as DNA damage response, TGF-β, NF-κB and Notch signaling pathways (Ramakrishna et al., 2011; Schoenfeld et al., 2004; Wu et al., 2014; Sun et al., 2010; Al-Salihi et al., 2012). Several substrates have been linked to USP11, including BRCA2, IκBα and promyelocytic leukemia protein (PML) (Ramakrishna et al., 2011; Schoenfeld et al., 2004; Wu et al., 2014; Sun et al., 2010; Al-Salihi et al., 2012). Regulation of BRCA2 by USP11 in response to DNA damage signal leads to an enhanced survivability for cancer cells (Schoenfeld et al., 2004). USP11 could counteract ubiquitylation of IκB thereby suppressing NFκB activation (Sun et al., 2010). The role of USP11 in modulating TGF-β signaling is through deubiquitylation of the type I TGF-β receptor ALK5 (Al-Salihi et al., 2012). In addition, USP11 could regulate PML-mediated purchase Sulfo-NHS-LC-Biotin tumor pathogenesis through stabilization of PML via antagonizing RNF4-facilitated PML ubiquitylation (Wu et al., 2014). Recent pathological studies further revealed the correlation of abnormal accumulation of USP11 with poor prognosis of breast cancer (Bayraktar et al., 2013). However, how exactly USP11 involves in breast cancer development and what is its deregulation of downstream substrate contributes to mammary tumorigenesis remains unknown. Thus, the identification of USP11 to be a potent player in promoting transformation of mammary gland epithelial cells and further elucidation of the mechanism by which USP11 regulates XIAP in promoting breast tumor initiation could advance our knowledge of molecular basis of cancer formation and provide novel target for anti-cancer therapy. X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis (IAP) family. XIAP has been initially identified for its role in blocking apoptosis upon inhibition of the activation of caspase-9, -3 and -7 through the XIAP-mediated protein degradation (Deveraux and Reed, 1999). Previous studies demonstrated the role of XIAP in regulating various cellular processes, including TGF-β signaling, NF-κB pathway, autophagy and inflammatory responses (Birkey Reffey et al., 2001; Gyrd-Hansen et al., 2008; Huang et al., 2013; Krieg et al., 2009). Mutations of XIAP in human have been linked to X-linked lymphoproliferative syndrome type 2 (XLP-2), a rare primary immunodeficiency (Rigaud et al., 2006). Aberrant stabilization of XIAP is thought to be one of the reasons for chemoresistance (Merlo and Cecconi, 2013; Schimmer et al., 2006). Recent studies revealed that the growth factor-induced phosphorylation of XIAP by AKT leads to the stabilization of XIAP through inhibiting its auto-ubiquitylation, which, in turn, leads to the inhibition of autophagy and tumorigenesis (Huang et al., 2013). Moreover, abnormal accumulated XIAP protein was observed in various types of human cancers such as leukemia, clear-cell renal carcinoma, prostate cancer, hepatocellular carcinoma and breast cancer, suggesting its oncogenic role in tumorigenesis (Schimmer et al., 2006; Xu et al., 2014; Berezovskaya et al., 2005; Mehrotra et al., 2010; Shi et al., 2008). Our identification of deubiquitylation of XIAP by USP11 adds up a novel layer for XIAP regulation. Characterization of relevance of USP11-XIAP axis in breast cancer initiation, progression and sensitization of breast cancer cell to chemodrugs could provide new strategy for anti-cancer therapy.
Materials and Methods
Results
Discussion Previous studies have implicated USP11 in tumorigenesis, although the underlying mechanism remained unclear. The work presented here establishes the inhibitor of apoptosis XIAP as a target of the deubiquitinase USP11 in human cells and xenograft mouse model, and provides concrete evidence for the coordinated-regulation of XIAP by its autoubiquitylation and USP11, to favor its deubiquitylation or stabilization, thus causing/assisting USP11-mediated tumor transformation. Accumulation of XIAP due to abrogated elevation of USP11 promotes tumor formation as well as progression because of its inhibition of anoikis in mammary gland epithelial cells and apoptosis in cancer cells, which enhances the escape of cells from regulated death. XIAP is directly bound to USP11 as shown here by both experimental and computational examinations. Our experiments in which USP11 was either overexpressed or depleted have documented the role of USP11 in XIAP stabilization and in determining the transformation of human mammary gland epithelial cells into cancer cells. These studies indicate that the DUB USP11 acts as a mediator of tumorigenesis by counteracting XIAP degradation and thus preventing the apoptotic response of the cells (Fig. 8).