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Reviews

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

Anupama Pal, Matthew A. Young and Nicholas J. Donato
DOI: 10.1158/0008-5472.CAN-14-1211 Published September 2014

Abstract

The ubiquitin–proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor–mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. Cancer Res; 74(18); 4955–66. ©2014 AACR.

Introduction

Most of the current molecular cancer therapies target protein kinases and mediate their antitumor activity through the deactivation of an aberrantly expressed, tumor-dependent, or unregulated target enzyme. Clinically successful kinase-targeting examples include Herceptin (Her2), imatinib (Bcr-Abl and c-Kit), vemurafenib (BRAF), and ibrutinib (BTK; ref. 1). However, kinase inhibition has restricted application and limited long-standing efficacy, as intrinsic resistance reduces benefit to only a fraction of patients and most responders will acquire resistance due to additional mutations or activation of compensating pathways (1). A deeper understanding of the molecular pathways associated with cancer has implicated posttranslation regulation through ubiquitination/deubiquitination of many target proteins as an additional and attractive targeted therapeutic approach.

Ubiquitin Proteasome System-Targeted Anticancer Therapeutics

Covalent attachment of ubiquitin, a 76–amino acid protein, to a target protein is a means of regulating protein half-life, localization, and activity. Because protein homeostasis is essential for the survival of all cells, but more essential to cancer cells, modulation of individual ubiquitin–proteasome system (UPS) components may present an opportunity for therapeutic targeting. As proof-of-principle, many compounds with proteasome inhibitory activity have been developed, including bortezomib (or Velcade; Millenium Pharmaceuticals), which is a synthetic dipeptide boronic acid that reversibly inhibits the chymotryptic-like activity of the 20S enzymatic core of the proteasome and induces apoptosis in several malignancies. Velcade is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with mantle cell lymphoma and multiple myeloma, even those resistant to doxorubicin, mitoxantrone, melphalan, and dexamethasone, and is commonly used in combination with many of these agents (2). Amplified protein synthesis (immunoglobulin) in many myeloma cells may underlie their clinical sensitivity to bortezomib and other proteasome inhibitors as most solid tumors do not have a similar commitment to elevated protein synthesis and are not clinically responsive to these drugs. This narrow therapeutic application, combined with some toxicity (sensory neuropathy), may be circumvented by novel proteasome inhibitory molecules (2).

Deubiquitinases as Emerging Targets for Anticancer therapeutics

Targeted inhibition of ubiquitin-conjugating enzymes and ligases could provide another therapeutic avenue. Inhibition of NEDD8-associated E1 enzyme by MLN4924, E2 enzyme hCdc34 by CC0651, and E3 ligase MDM2 by RITA (NSC652287) and MI-219 reflects this ongoing effort (3). Deubiquitinases (DUB) are another class of emerging anticancer target that regulate specific substrate proteins by reversing their ubiquitination through the hydrolysis of isopeptide or α-peptide bonds linking ubiquitin to the target protein (4). If the target protein is an oncogene, the DUB activity of the associated DUB may stabilize its cellular expression and supports identification of DUB inhibitors that could reestablish normal protein turnover, location, or activity (4). This approach may also avoid the deleterious side effects associated with direct targeting of the proteasome. With around 55 members, ubiquitin-specific proteases (USP) comprise the largest and most diverse family of DUBs. Genetic and/or functional analysis have placed USPs in the category of cancer-associated proteases, and their unique biochemical structures have made them desirable targets for anticancer therapies. More than 30 USPs have been associated with cancer directly or indirectly. These numbers are not surprising, considering the various critical cellular functions regulated by different USPs and the diversity of substrates used and regulated by them. A comprehensive list of USPs altered in different cancers is provided in Table 1.

View this table:
Table 1.

A comprehensive list of the USPs implicated in human cancers

Role of Ubiquitin Specific Proteases in Cancer

USP-associated mutations and gene fusions in hematologic malignancies

Recurrent mutations of USPs are rare in cancer with the exception of CYLD. Germline mutations of the tumor-suppressor gene CYLD are prevalent in familial cylindromatosis, a genetic condition that leads to predisposition for developing multiple skin tumors (5). The only known chromosomal translocation involving a USP is the fusion of the promoter of CDH11 to the full-length USP6 gene that leads to upregulated transcript levels of USP6 (6). USP gene fusions are reported for USP42 and USP16 that are fusion gene partners with RUNX, which has high-frequency gene alterations in hematologic diseases such as chronic myelomonocytic leukemia and acute myeloid leukemia (AML; refs. 7, 8). USP18 transcript levels are upregulated in mice expressing the AML fusion protein AML1–ETO (9). USP33/VDU1 mRNA levels are overexpressed in B-cell acute lymphoblastic leukemias (10). Increased mRNA levels of USP50 have also been reported in AML (11). Upregulated transcript levels of USP9x have been correlated with poor prognosis in multiple myeloma and are associated with Mcl-1 accumulation in patients with follicular lymphoma (12). Thus, USPs are repeatedly implicated in many hematologic malignancies.

USPs as important regulators of p53 signaling and DNA damage response

An important aspect of hematopoietic tumors is that p53 mutations are rare; however, p53 levels are tightly regulated by ubiquitination/deubiquitination (13). Thus, modulation of p53 levels in these tumors can provide a therapeutic advantage by inducing p53-dependent apoptosis and cell-cycle arrest. A key molecule involved in p53 ubiquitination is the E3 ligase MDM2, which is a negative regulator of p53 stability (13). Although USP7 and USP2a have been reported to deubiquitinate MDM2, leading to degradation of p53 and antiapoptotic activity, USP7 and USP10 can directly deubiquitinate p53 under specific conditions (14, 15). Under normal conditions, USP7 stabilizes MDM2 and leads to degradation of p53, whereas USP10 deubiquitinates and stabilizes p53. In response to DNA damage and following ATM kinase activation, the substrate preference of USP7 switches from MDM2 to p53, leading to its stabilization (14, 16). Similarly, in response to DNA damage, USP10 is stabilized in an ATM kinase-dependent manner and a portion of it translocates to the nucleus where it joins USP7 in deubiquitinating and stabilizing p53. Other USPs known to regulate p53 levels in the cell include USP4 and USP5 (17, 18). USP4 reduces p53 levels in the cell through direct binding and deubiquitination of the E3 ligase HUWE1, also called MULE or ARF-BP1 (17). USP5 depletion in the cell leads to accumulation of unanchored polyubiquitin chains, competing with p53 for proteasomal destruction, which results in nuclear accumulation of p53 and transcriptional activation of p53 target genes (18). Very recently, USP15 was shown to target MDM2 with effects on the stability of both p53 and the T-cell transcription factor, NFATc. Thus, USP15 inhibition could result in direct tumor cell apoptosis and increased T-cell responsiveness (19).

Because ubiquitination/deubiquitination is also an important mechanism essential for regulation of the DNA-damage repair (DDR), a large number of USPs are implicated in regulating or coordinating DDR. USP3, USP7, USP10, USP11, USP16, USP21, and USP22 are reported to regulate DDR sensor proteins. USP1, USP2, USP4, USP7, USP10, USP11, USP24, USP29, and USP47 are directly implicated in the regulation of DDR repair proteins (20). Single-strand DNA breaks are repaired by nucleotide excision repair (NER) and base excision repair (BER) pathways that deal with various DNA helix-distorting lesions and single-strand breaks; mismatch repair pathways that repair base mismatches and insertions/deletions; the nonhomologous end-joining pathway (NHEJ) and/or homologous recombination (HR) pathways, and the Fanconi anemia (FA) pathway, which in conjunction with certain HR factors act to recognize and repair inter-strand cross-links (ICL) DNA lesions. USP1 and USP7 act in multiple DDR pathways. USP1 removes monoubiquitin from FANCD2 and PCNA, and thus regulate ICL and trans-lesional DNA synthesis (20). USP1 levels are well regulated during the cell cycle and their depletion leads to genomic instability. USP1 knockouts show defects in FA and HR repair (21). Like USP1, USP7 also acts in multiple DDR pathways. In response to DSB, the DSB sensor kinase ATM is activated, which leads to downregulation of USP7S, a USP7 isoform, resulting in the activation of a p53 response and regulation of the G2–M checkpoint (20). USP7 is also a major regulator of the oxidative stress response. Through its deubiquitinating activity, USP7 can modulate FOXO4 transcriptional activity in response to oxidative stress. USP7 can also modulate BER of oxidative lesions through chromatin remodeling directly by deubiquitination of histones, or indirectly by regulating the cellular levels of E3 ubiquitin ligases involved in histone ubiquitination. USP29 also mediates the oxidative stress response by stabilizing p53 in a FBP/JTV1–dependent manner. USP7 is also implicated in transcription-coupled NER (TCNER), a subpathway of NER that efficiently removes highly toxic RNA polymerase II blocking lesions on DNA causing Cockayne syndrome and UV-sensitive syndrome (UVSS). Apart from USP7, USP47 is the only other DUB that is reported to regulate BER through the stabilization of newly synthesized polymerase β (Pol-β). USP47-silenced cells show aberrant DDR growth inhibition and chemosensitization. USP3 and USP16 deubiquitinate histone H2A and USP16 also opposes the RNF8–RNF18 pathway–mediated DDR to double-strand breaks (DSB), leading to accumulation of replication stress in the cell. USP24 stabilizes DDB2, also called p48, which is an important protein in the recognition and repair of UV-induced lesions in the NER pathway (22). In response to DNA damage, USP28 binds with 53BP1 and its loss induces ionizing radiation–induced apoptosis. USP44 has been identified as a DUB critical for spindle assembly checkpoint activity and in centrosome regulation. USP44-deficient mice are susceptible to spontaneous tumors of the lung, supporting a role for USP44 as a tumor-suppressor gene (reviewed in ref. 20). These findings are especially noteworthy because current radiation and chemotherapy regimens used for the treatment of various cancers rely heavily on inducing DNA damage to the cancer cell. Developing specific or even partially specific inhibitors that can target several USPs, resulting in cell-cycle arrest or apoptosis, in the cancer cell may be advantageous.

USPs as regulators of cancer-associated pathways

USPs are also implicated as important regulators of several cancer-associated pathways. The NF-κB pathway is constitutively activated in a vast range of cancers and is implicated in tumorigenesis and metastasis. Several USPs are reported as negative regulators of NF-κB signaling. CYLD binds to the NEMO component of the IκB kinase complex and regulates its activity through deubiquitination of TRAF2. Inhibition of CYLD increases resistance to apoptosis, an effect that can be relieved by inhibiting NF-κB activity using aspirin derivatives (23). USP31 has also been identified as a TRAF2-interacting protein that regulates NF-κB activation by members of the TNF receptor superfamily (24). USP4 directly interacts and exerts deubiquitinating activity on multiple NF-κB pathway–associated molecules, such as TRAF2, TRAF6, and TAK1 kinase, and negatively regulates TNFα and IL1β-induced cancer cell migration. USP4 negatively regulates receptor-interacting protein 1 (RIP1)–mediated NF-κB activation and promotes TNFα-induced apoptosis in head and neck squamous cell carcinomas through direct interaction with RIP1 and deubiquitination of K63-linked ubiquitin from RIP1 (25). USP11 mediates downregulation of TNFα-mediated NF-κB activation through modulation of IκBα stability by its deubiquitination (26). USP14 removes the ubiquitin chain of I-κB, thereby inducing I-κB degradation and increasing cytokine release in lung epithelial cells (27). COP9 signalosome (CSN) regulates assembly and activity of cullin-RING ubiquitin ligases (CRL), which are involved in the ubiquitination of Iκ-α. USP15 is identified as a CSN-associated DUB that reverses the ubiquitinating activity of CSN on IκBα, thus negatively regulating NF-κB signaling (28).

Several USPs are implicated in the regulation of TGFβ signaling at various levels of the pathway. USP4, USP11, and USP15 interact with the TGFβ receptor I, deubiquitinate, and stabilize this receptor to engage sustained Smad activation, resulting in enhancement of TGFβ signaling. Inhibiting USP4 and USP11 inhibits TGFβ-mediated epithelial–mesenchymal transition (EMT) and invasion in breast cancer while USP15 inhibition blocks EMT and invasion in glioblastomas (29). USP4 has also been shown to drive cross-talk between TGFβ and AKT signaling in breast cancer. Inhibiting USP4 suppresses AKT-mediated breast cancer cell migration. These findings underscore the relevance of USP4 in the pathway as AKT activation has been associated with poor prognosis in breast cancer (29). USP9X reverses the mono-ubiquitination of Smad4 at Lys 519, a modification that prevents its binding to phosphorylated Smad2 and inhibition of TGFβ signaling. Thus, Smad4 deubiquitination by USP9X reinstates TGFβ signaling (12). USP9X can also deubiquitinate E3 ubiquitin ligase SMURF1, whose substrates include TGFβ receptor and coreceptor Smads (30). Recent findings in our laboratory show an oncogenic potential of USP9X in established breast cancer cells and inhibiting USP9X inhibits cell growth in tumorigenic cells and induces apoptosis in triple-negative breast cancers (Unpublished Data). Thus, there is accumulating evidence in favor of therapeutic targeting of USPs like USP4, USP15, and USP9X in breast cancer.

Inhibitor of differentiation (ID) proteins (ID1-4) regulate differentiation and maintain stem cell fate through inhibition of basic–helix–loop–helix transcription factors. ID protein levels are deregulated during cancer and have been associated with an aggressive clinical phenotype and poor patient outcomes. The expression levels of ID proteins are tightly regulated through ubiquitination by the APC/Cdh1 E3 ligase complex, which leads to proteasomal degradation and shorter half-life of ID proteins in the cell (31). Recently, USP1 was shown to stabilize ID1, ID2, and ID3 protein expression levels in normal and malignant stem cell populations through its deubiquitinating activity. USP1 was found to be overexpressed in a subset of osteosarcomas where it stabilized ID1, ID2, and ID3, leading to repression of p21 levels and aberrant osteogenic differentiation (32). USP1 abundance correlated with ID2 protein abundance levels in human osteosarcoma tumors. Thus, small molecule–mediated targeting of USP1 may provide an additional modality for treatment of cancer through modulation of ID proteins. Despite the growing interest in USPs and in acquiring USP inhibitors, their development has been hampered by some of the biochemical properties of the USPs themselves and mostly unavailable three-dimensional (3D) structures. To date, only seven USPs have defined 3D structures (Table 1). USPs can range in size from 350 to 3,500 amino acids. They comprise a central catalytic domain, which could be 295 to 850 amino acids long and shows an average 22% identity among USPs and many different additional domains like the ubiquitin-like domain in USP7 and USP14. Such versatility in this small family of DUBs could be a boon in the development of partially selective or specific inhibitors and will benefit from unraveling the structural information of more USPs.

Development of Small Molecule Inhibitors against USPs

USP7 inhibitors: HBX 41, 108, and P5091

Among the earliest reported DUB inhibitors are cyclopentenone prostaglandins that induce apoptosis and also increase the cellular content of poly-ubiquitinated proteins, suggesting they are nonselective DUB inhibitors (3). A small molecule discovered in screens for DUB inhibitors, PR-619, is selective for DUBs over other cysteine proteases, but inhibits all DUBs tested with moderate potency. More recently, HBX 41,108, which was originally reported to be a USP7 inhibitor, was confirmed to be a nonselective DUB inhibitor. HBX 41,108 stabilizes p53 in HEK293 cells and induces caspase-3 and PARP cleavage in both p53+/+ and p53−/− HCT-116 cells. The specificity of HBX 41,108 is limited as it can also inhibit USP5, USP8, UCH-L3, and caspase-3 with a potency (70–200 nmol/L) greater than its activity against USP7 (530 nmol/L). However, because of the critical regulatory functions played by USP7 in the cell there is tremendous interest in developing USP7-specific inhibitors (33). Progenra has identified the novel P5091 small-molecule USP7-specific inhibitor that can stabilize p53, inhibit cancer cell proliferation, and is an active antitumor agent in various tumor models. P5091 induces apoptosis in multiple myeloma cells resistant to conventional and bortezomib therapies (34). P5091 is well-tolerated in animals, inhibits tumor growth, prolongs survival, and triggers synergistic anti–multiple myeloma activity in combination with other chemotherapeutic agents such as lenalidomide, HDAC inhibitor, or dexamethasone. Hit-to-lead optimization identified additional analogs of P5091 (e.g., aqueous soluble derivative P045204) that increases the steady-state levels of p53 and its transcriptional target p21 in a time-dependent manner in HCT-116 cells.

USP14 inhibitors: b-AP15

b-AP15, also known as VLX1500, is a unique class of proteasome inhibitor that inhibits the activity of the 19S regulatory particle–associated DUBs, UCHL5, a ubiquitin C terminal hydrolase, and USP14. b-AP15 induces apoptosis in tumor cells irrespective of their mutant p53 status and BCL2 overexpression and is effective in inhibiting tumor progression in multiple solid tumor mouse models and dissemination of an in vivo AML model. The apoptotic effects of b-AP15 are mediated through the induction of oxidative and endoplasmic reticulum (ER) stress in response to b-AP15–mediated accumulation of poly-ubiquitinated proteins (35).

USP1-UAF1 inhibitors: Pimozide, GW7647, and ML323

Pimozide and GW7647 inhibit USP1–UAF1 complex through noncompetitive binding, which provides for more selectivity and specificity toward USP1–UAF1. These inhibitors act in synergy with cisplatin to inhibit cell proliferation in cisplatin-resistant non–small cell lung cancer cells (36). Pimozide also inhibits leukemic cell growth through degradation of USP1 substrate ID1 (37). ML323 is another highly potent inhibitor of the USP1–UAF1 complex that provides for excellent selectivity against DUBs. In non–small cell lung cancer and osteosarcomas, ML323 potentiates cisplatin-induced cytotoxicity (38). ML323-mediated inhibition of USP1 inhibits deubiquitination of FANCD2 and PCNA and compromises TLS and FA pathways (38). Thus, ML323 may provide a means to sensitize cancer cells to platinum-based therapies.

USP9X inhibitors: WP1130 and its derivatives

In our laboratory, we described and developed the small-molecule inhibitor WP1130, also known as Degrasyn, which was derived from a compound with JAK2 kinase–inhibitory activity. WP1130 rapidly induces accumulation of poly-ubiquitinated proteins, resulting in induction of apoptosis. WP1130 is a partially selective inhibitor that directly inhibits the deubiquitinating activity of USP9X, USP5, and USP14, all of which regulate survival protein stability and proteasome function. In several studies done in the recent past, USP9X inhibition by WP1130 promotes apoptosis by reducing MCL-1 levels and increased tumor cell sensitivity to chemotherapy (39). Recently, USP9X inhibition by WP1130 was shown to inhibit the growth of ERG-positive tumors in vitro and in mouse xenograft models of prostate cancer (40). Our laboratory has been actively engaged in identifying derivatives with greater selectivity, activity, and drug-like properties. We recently identified and are developing a compound with improved specificity toward USP9X and antitumor activity in mouse models of myeloma, lymphoma, and melanoma (unpublished data).

Conclusively, there is accumulating experimental evidence that a large number of USPs could be targeted for anticancer therapeutics. Early evidence for antitumor efficacy with the currently available USP inhibitors is more than encouraging and sets the stage for the development of selective, as well as partially selective, small-molecule DUB inhibitors.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

  • Received April 18, 2014.
  • Revision received July 7, 2014.
  • Accepted July 8, 2014.

References

  1. 1.↵
    1. Zhang J,
    2. Yang PL,
    3. Gray NS
    . Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009;9:28–39.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Chen D,
    2. Frezza M,
    3. Schmitt S,
    4. Kanwar J,
    5. Dou QP
    . Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 2011;11:239–53.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Mattern MR,
    2. Wu J,
    3. Nicholson B
    . Ubiquitin-based anticancer therapy: carpet bombing with proteasome inhibitors vs surgical strikes with E1, E2, E3, or DUB inhibitors. Biochim Biophys Acta 2012;1823:2014–21.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Hussain S,
    2. Zhang Y,
    3. Galardy PJ
    . DUBs and cancer: the role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors. Cell Cycle 2009;8:1688–97.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Bignell GR,
    2. Warren W,
    3. Seal S,
    4. Takahashi M,
    5. Rapley E,
    6. Barfoot R,
    7. et al.
    Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 2000;25:160–5.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Oliveira AM,
    2. Chou MM,
    3. Perez-Atayde AR,
    4. Rosenberg AE
    . Aneurysmal bone cyst: a neoplasm driven by upregulation of the USP6 oncogene. J Clin Oncol 2006;24:e1.
    OpenUrlFREE Full Text
  7. 7.↵
    1. Gelsi-Boyer V,
    2. Trouplin V,
    3. Adelaide J,
    4. Aceto N,
    5. Remy V,
    6. Pinson S,
    7. et al.
    Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer 2008;8:299.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Masetti R,
    2. Togni M,
    3. Astolfi A,
    4. Pigazzi M,
    5. Indio V,
    6. Rivalta B,
    7. et al.
    Whole transcriptome sequencing of a paediatric case of de novo acute myeloid leukaemia with del(5q) reveals RUNX1-USP42 and PRDM16-SKI fusion transcripts. Br J Haematol. 2014 Mar 27 [Epub ahead of print].
  9. 9.↵
    1. Liu LQ,
    2. Ilaria R Jr.,
    3. Kingsley PD,
    4. Iwama A,
    5. van Etten RA,
    6. Palis J,
    7. et al.
    A novel ubiquitin-specific protease, UBP43, cloned from leukemia fusion protein AML1-ETO–expressing mice, functions in hematopoietic cell differentiation. Mol Cell Biol 1999;19:3029–38.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. De Pitta C,
    2. Tombolan L,
    3. Campo Dell'Orto M,
    4. Accordi B,
    5. te Kronnie G,
    6. Romualdi C,
    7. et al.
    A leukemia-enriched cDNA microarray platform identifies new transcripts with relevance to the biology of pediatric acute lymphoblastic leukemia. Haematologica 2005;90:890–8.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Figueroa ME,
    2. Lugthart S,
    3. Li Y,
    4. Erpelinck-Verschueren C,
    5. Deng X,
    6. Christos PJ,
    7. et al.
    DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010;17:13–27.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Schwickart M,
    2. Huang X,
    3. Lill JR,
    4. Liu J,
    5. Ferrando R,
    6. French DM,
    7. et al.
    Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 2010;463:103–7.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Hock AK,
    2. Vousden KH
    . The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta 2014;1843:137–49.
    OpenUrlCrossRef
  14. 14.↵
    1. Meulmeester E,
    2. Pereg Y,
    3. Shiloh Y,
    4. Jochemsen AG
    . ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 2005;4:1166–70.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Stevenson LF,
    2. Sparks A,
    3. Allende-Vega N,
    4. Xirodimas DP,
    5. Lane DP,
    6. Saville MK
    . The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J 2007;26:976–86.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Yuan J,
    2. Luo K,
    3. Zhang L,
    4. Cheville JC,
    5. Lou Z
    . USP10 regulates p53 localization and stability by deubiquitinating p53. Cell 2010;140:384–96.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Zhang X,
    2. Berger FG,
    3. Yang J,
    4. Lu X
    . USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO J 2011;30:2177–89.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Dayal S,
    2. Sparks A,
    3. Jacob J,
    4. Allende-Vega N,
    5. Lane DP,
    6. Saville MK
    . Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. J Biol Chem 2009;284:5030–41.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Zou Q,
    2. Jin J,
    3. Hu H,
    4. Li HS,
    5. Romano S,
    6. Xiao Y,
    7. et al.
    USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 2014;15:562–70.
    OpenUrlPubMed
  20. 20.↵
    1. Jacq X,
    2. Kemp M,
    3. Martin NM,
    4. Jackson SP
    . Deubiquitylating enzymes and DNA damage response pathways. Cell Biochem Biophys 2013;67:25–43.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Kim JM,
    2. Parmar K,
    3. Huang M,
    4. Weinstock DM,
    5. Ruit CA,
    6. Kutok JL,
    7. et al.
    Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell 2009;16:314–20.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Zhang L,
    2. Lubin A,
    3. Chen H,
    4. Sun Z,
    5. Gong F
    . The deubiquitinating protein USP24 interacts with DDB2 and regulates DDB2 stability. Cell Cycle 2012;11:4378–84.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Harhaj EW,
    2. Dixit VM
    . Regulation of NF-kappaB by deubiquitinases. Immunol Rev 2012;246:107–24.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Tzimas C,
    2. Michailidou G,
    3. Arsenakis M,
    4. Kieff E,
    5. Mosialos G,
    6. Hatzivassiliou EG
    . Human ubiquitin specific protease 31 is a deubiquitinating enzyme implicated in activation of nuclear factor-kappaB. Cell Signal 2006;18:83–92.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Hou X,
    2. Wang L,
    3. Zhang L,
    4. Pan X,
    5. Zhao W
    . Ubiquitin-specific protease 4 promotes TNF-alpha–induced apoptosis by deubiquitination of RIP1 in head and neck squamous cell carcinoma. FEBS Lett 2013;587:311–6.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Sun W,
    2. Tan X,
    3. Shi Y,
    4. Xu G,
    5. Mao R,
    6. Gu X,
    7. et al.
    USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal 2010;22:386–94.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Mialki RK,
    2. Zhao J,
    3. Wei J,
    4. Mallampalli DF,
    5. Zhao Y
    . Overexpression of USP14 protease reduces I-kappaB protein levels and increases cytokine release in lung epithelial cells. J Biol Chem 2013;288:15437–41.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Schweitzer K,
    2. Bozko PM,
    3. Dubiel W,
    4. Naumann M
    . CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. EMBO J 2007;26:1532–41.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Aggarwal K,
    2. Massague J
    . Ubiquitin removal in the TGF-beta pathway. Nat Cell Biol 2012;14:656–7.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Xie Y,
    2. Avello M,
    3. Schirle M,
    4. McWhinnie E,
    5. Feng Y,
    6. Bric-Furlong E,
    7. et al.
    Deubiquitinase FAM/USP9X interacts with the E3 ubiquitin ligase SMURF1 protein and protects it from ligase activity-dependent self-degradation. J Biol Chem 2013;288:2976–85.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Nair R,
    2. Teo WS,
    3. Mittal V,
    4. Swarbrick A
    . ID proteins regulate diverse aspects of cancer progression and provide novel therapeutic opportunities. Mol Ther. 2014 May 14. [Epub ahead of print].
  32. 32.↵
    1. Williams SA,
    2. Maecker HL,
    3. French DM,
    4. Liu J,
    5. Gregg A,
    6. Silverstein LB,
    7. et al.
    USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell 2011;146:918–30.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Colland F,
    2. Formstecher E,
    3. Jacq X,
    4. Reverdy C,
    5. Planquette C,
    6. Conrath S,
    7. et al.
    Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther 2009;8:2286–95.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Chauhan D,
    2. Tian Z,
    3. Nicholson B,
    4. Kumar KG,
    5. Zhou B,
    6. Carrasco R,
    7. et al.
    A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 2012;22:345–58.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Tian Z,
    2. D'Arcy P,
    3. Wang X,
    4. Ray A,
    5. Tai YT,
    6. Hu Y,
    7. et al.
    A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 2014;123:706–16.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Chen J,
    2. Dexheimer TS,
    3. Ai Y,
    4. Liang Q,
    5. Villamil MA,
    6. Inglese J,
    7. et al.
    Selective and cell-active inhibitors of the USP1/UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chem Biol 2011;18:1390–400.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Mistry H,
    2. Hsieh G,
    3. Buhrlage SJ,
    4. Huang M,
    5. Park E,
    6. Cuny GD,
    7. et al.
    Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther 2013;12:2651–62.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Liang Q,
    2. Dexheimer TS,
    3. Zhang P,
    4. Rosenthal AS,
    5. Villamil MA,
    6. You C,
    7. et al.
    A selective USP1–UAF1 inhibitor links deubiquitination to DNA damage responses. Nat Chem Biol 2014;10:298–304.
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Kapuria V,
    2. Peterson LF,
    3. Fang D,
    4. Bornmann WG,
    5. Talpaz M,
    6. Donato NJ
    . Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res 2010;70:9265–76.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Wang S,
    2. Kollipara RK,
    3. Srivastava N,
    4. Li R,
    5. Ravindranathan P,
    6. Hernandez E,
    7. et al.
    Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc Natl Acad Sci U S A 2014;111:4251–6.
    OpenUrlAbstract/FREE Full Text
  41. 41.
    1. Komander D,
    2. Lord CJ,
    3. Scheel H,
    4. Swift S,
    5. Hofmann K,
    6. Ashworth A,
    7. et al.
    The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell 2008;29:451–64.
    OpenUrlCrossRefPubMed
  42. 42.
    1. Ke H,
    2. Augustine CK,
    3. Gandham VD,
    4. Jin JY,
    5. Tyler DS,
    6. Akiyama SK,
    7. et al.
    CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and beta1-integrin signaling pathways. J Invest Dermatol 2013;133:221–9.
    OpenUrlCrossRefPubMed
  43. 43.
    1. Pannem RR,
    2. Dorn C,
    3. Ahlqvist K,
    4. Bosserhoff AK,
    5. Hellerbrand C,
    6. Massoumi R
    . CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma. Carcinogenesis 2014;35:461–8.
    OpenUrlAbstract/FREE Full Text
  44. 44.
    1. Reiley WW,
    2. Jin W,
    3. Lee AJ,
    4. Wright A,
    5. Wu X,
    6. Tewalt EF,
    7. et al.
    Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 2007;204:1475–85.
    OpenUrlAbstract/FREE Full Text
  45. 45.
    1. Nijman SM,
    2. Huang TT,
    3. Dirac AM,
    4. Brummelkamp TR,
    5. Kerkhoven RM,
    6. D'Andrea AD,
    7. et al.
    The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell 2005;17:331–9.
    OpenUrlCrossRefPubMed
  46. 46.
    1. Renatus M,
    2. Parrado SG,
    3. D'Arcy A,
    4. Eidhoff U,
    5. Gerhartz B,
    6. Hassiepen U,
    7. et al.
    Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure 2006;14:1293–302.
    OpenUrlCrossRefPubMed
  47. 47.
    1. Ernst A,
    2. Avvakumov G,
    3. Tong J,
    4. Fan Y,
    5. Zhao Y,
    6. Alberts P,
    7. et al.
    A strategy for modulation of enzymes in the ubiquitin system. Science 2013;339:590–5.
    OpenUrlAbstract/FREE Full Text
  48. 48.
    1. Benassi B,
    2. Flavin R,
    3. Marchionni L,
    4. Zanata S,
    5. Pan Y,
    6. Chowdhury D,
    7. et al.
    MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer. Cancer Discov 2012;2:236–47.
    OpenUrlAbstract/FREE Full Text
  49. 49.
    1. He X,
    2. Li Y,
    3. Li C,
    4. Liu LJ,
    5. Zhang XD,
    6. Liu Y,
    7. et al.
    USP2a negatively regulates IL-1beta- and virus-induced NF-kappaB activation by deubiquitinating TRAF6. J Mol Cell Biol 2013;5:39–47.
    OpenUrlAbstract/FREE Full Text
  50. 50.
    1. Tao BB,
    2. He H,
    3. Shi XH,
    4. Wang CL,
    5. Li WQ,
    6. Li B,
    7. et al.
    Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade. J Clin Neurosci 2013;20:717–20.
    OpenUrlCrossRefPubMed
  51. 51.
    1. Nicassio F,
    2. Corrado N,
    3. Vissers JH,
    4. Areces LB,
    5. Bergink S,
    6. Marteijn JA,
    7. et al.
    Human USP3 is a chromatin modifier required for S phase progression and genome stability. Curr Biol 2007;17:1972–7.
    OpenUrlCrossRefPubMed
  52. 52.
    1. Raychaudhuri P
    . USP3 controls BRCA1 “foci”. Cell Cycle 2014;13:183.
    OpenUrlCrossRefPubMed
  53. 53.
    1. Sharma N,
    2. Zhu Q,
    3. Wani G,
    4. He J,
    5. Wang QE,
    6. Wani AA
    . USP3 counteracts RNF168 via deubiquitinating H2A and gammaH2AX at lysine 13 and 15. Cell Cycle 2014;13:106–14.
    OpenUrlCrossRefPubMed
  54. 54.
    1. Luna-Vargas MP,
    2. Faesen AC,
    3. van Dijk WJ,
    4. Rape M,
    5. Fish A,
    6. Sixma TK
    . Ubiquitin-specific protease 4 is inhibited by its ubiquitin-like domain. EMBO Rep 2011;12:365–72.
    OpenUrlAbstract/FREE Full Text
  55. 55.
    1. Fan YH,
    2. Yu Y,
    3. Mao RF,
    4. Tan XJ,
    5. Xu GF,
    6. Zhang H,
    7. et al.
    USP4 targets TAK1 to downregulate TNFalpha-induced NF-kappaB activation. Cell Death Differ 2011;18:1547–60.
    OpenUrlCrossRefPubMed
  56. 56.
    1. Hock AK,
    2. Vigneron AM,
    3. Carter S,
    4. Ludwig RL,
    5. Vousden KH
    . Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J 2011;30:4921–30.
    OpenUrlAbstract/FREE Full Text
  57. 57.
    1. Zhang L,
    2. Zhou F,
    3. Drabsch Y,
    4. Gao R,
    5. Snaar-Jagalska BE,
    6. Mickanin C,
    7. et al.
    USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor. Nat Cell Biol 2012;14:717–26.
    OpenUrlCrossRefPubMed
  58. 58.
    1. Zhao B,
    2. Schlesiger C,
    3. Masucci MG,
    4. Lindsten K
    . The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway. J Cell Mol Med 2009;13:1886–95.
    OpenUrlCrossRefPubMed
  59. 59.
    1. Reyes-Turcu FE,
    2. Horton JR,
    3. Mullally JE,
    4. Heroux A,
    5. Cheng X,
    6. Wilkinson KD
    . The ubiquitin binding domain ZnF UBP recognizes the C-terminal diglycine motif of unanchored ubiquitin. Cell 2006;124:1197–208.
    OpenUrlCrossRefPubMed
  60. 60.
    1. Avvakumov GV,
    2. Walker JR,
    3. Xue S,
    4. Allali-Hassani A,
    5. Asinas A,
    6. Nair UB,
    7. et al.
    Two ZnF-UBP domains in isopeptidase T (USP5). Biochemistry 2012;51:1188–98.
    OpenUrlCrossRefPubMed
  61. 61.
    1. Izaguirre DI,
    2. Zhu W,
    3. Hai T,
    4. Cheung HC,
    5. Krahe R,
    6. Cote GJ
    . PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. Mol Carcinog 2012;51:895–906.
    OpenUrlCrossRefPubMed
  62. 62.
    1. Nakajima S,
    2. Lan L,
    3. Wei L,
    4. Hsieh CL,
    5. Rapic-Otrin V,
    6. Yasui A,
    7. et al.
    Ubiquitin-specific protease 5 is required for the efficient repair of DNA double-strand breaks. PLoS ONE 2014;9:e84899.
    OpenUrlCrossRefPubMed
  63. 63.
    1. Oliveira AM,
    2. Hsi BL,
    3. Weremowicz S,
    4. Rosenberg AE,
    5. Dal Cin P,
    6. Joseph N,
    7. et al.
    USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res 2004;64:1920–3.
    OpenUrlAbstract/FREE Full Text
  64. 64.
    1. Pringle LM,
    2. Young R,
    3. Quick L,
    4. Riquelme DN,
    5. Oliveira AM,
    6. May MJ,
    7. et al.
    Atypical mechanism of NF-kappaB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis. Oncogene 2012;31:3525–35.
    OpenUrlCrossRefPubMed
  65. 65.
    1. Ye Y,
    2. Pringle LM,
    3. Lau AW,
    4. Riquelme DN,
    5. Wang H,
    6. Jiang T,
    7. et al.
    TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB. Oncogene 2010;29:3619–29.
    OpenUrlCrossRefPubMed
  66. 66.
    1. Hu M,
    2. Li P,
    3. Li M,
    4. Li W,
    5. Yao T,
    6. Wu JW,
    7. et al.
    Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell 2002;111:1041–54.
    OpenUrlCrossRefPubMed
  67. 67.
    1. Hu M,
    2. Gu L,
    3. Li M,
    4. Jeffrey PD,
    5. Gu W,
    6. Shi Y
    . Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway. PLoS Biol 2006;4:e27.
    OpenUrlCrossRefPubMed
  68. 68.
    1. Sheng Y,
    2. Saridakis V,
    3. Sarkari F,
    4. Duan S,
    5. Wu T,
    6. Arrowsmith CH,
    7. et al.
    Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol 2006;13:285–91.
    OpenUrlCrossRefPubMed
  69. 69.
    1. Molland K,
    2. Zhou Q,
    3. Mesecar AD
    . A 2.2 A resolution structure of the USP7 catalytic domain in a new space group elaborates upon structural rearrangements resulting from ubiquitin binding. Acta Crystallogr F Struct Biol Commun 2014;70(Pt 3):283–7.
    OpenUrlCrossRefPubMed
  70. 70.
    1. Saridakis V,
    2. Sheng Y,
    3. Sarkari F,
    4. Holowaty MN,
    5. Shire K,
    6. Nguyen T,
    7. et al.
    Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein–Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell 2005;18:25–36.
    OpenUrlCrossRefPubMed
  71. 71.
    1. Cheon KW,
    2. Baek KH
    . HAUSP as a therapeutic target for hematopoietic tumors (review). Int J Oncol 2006;28:1209–15.
    OpenUrlCrossRefPubMed
  72. 72.
    1. Reverdy C,
    2. Conrath S,
    3. Lopez R,
    4. Planquette C,
    5. Atmanene C,
    6. Collura V,
    7. et al.
    Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Chem Biol 2012;19:467–77.
    OpenUrlCrossRefPubMed
  73. 73.
    1. Avvakumov GV,
    2. Walker JR,
    3. Xue S,
    4. Finerty PJ Jr.,
    5. Mackenzie F,
    6. Newman EM,
    7. et al.
    Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). J Biol Chem 2006;281:38061–70.
    OpenUrlAbstract/FREE Full Text
  74. 74.
    1. Samara NL,
    2. Ringel AE,
    3. Wolberger C
    . A role for intersubunit interactions in maintaining SAGA deubiquitinating module structure and activity. Structure 2012;20:1414–24.
    OpenUrlCrossRefPubMed
  75. 75.
    1. Kohler A,
    2. Zimmerman E,
    3. Schneider M,
    4. Hurt E,
    5. Zheng N
    . Structural basis for assembly and activation of the heterotetrameric SAGA histone H2B deubiquitinase module. Cell 2010;141:606–17.
    OpenUrlCrossRefPubMed
  76. 76.
    1. Berlin I,
    2. Higginbotham KM,
    3. Dise RS,
    4. Sierra MI,
    5. Nash PD
    . The deubiquitinating enzyme USP8 promotes trafficking and degradation of the chemokine receptor 4 at the sorting endosome. J Biol Chem 2010;285:37895–908.
    OpenUrlAbstract/FREE Full Text
  77. 77.
    1. Byun S,
    2. Lee SY,
    3. Lee J,
    4. Jeong CH,
    5. Farrand L,
    6. Lim S,
    7. et al.
    USP8 is a novel target for overcoming gefitinib resistance in lung cancer. Clin Cancer Res 2013;19:3894–904.
    OpenUrlAbstract/FREE Full Text
  78. 78.
    1. Panner A,
    2. Crane CA,
    3. Weng C,
    4. Feletti A,
    5. Fang S,
    6. Parsa AT,
    7. et al.
    Ubiquitin-specific protease 8 links the PTEN-Akt-AIP4 pathway to the control of FLIPS stability and TRAIL sensitivity in glioblastoma multiforme. Cancer Res 2010;70:5046–53.
    OpenUrlAbstract/FREE Full Text
  79. 79.
    1. Xia R,
    2. Jia H,
    3. Fan J,
    4. Liu Y,
    5. Jia J
    . USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS Biol 2012;10:e1001238.
    OpenUrlCrossRefPubMed
  80. 80.
    1. Cox JL,
    2. Wilder PJ,
    3. Gilmore JM,
    4. Wuebben EL,
    5. Washburn MP,
    6. Rizzino A
    . The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells. PLoS ONE 2013;8:e62857.
    OpenUrlCrossRefPubMed
  81. 81.
    1. Dupont S,
    2. Mamidi A,
    3. Cordenonsi M,
    4. Montagner M,
    5. Zacchigna L,
    6. Adorno M,
    7. et al.
    FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 2009;136:123–35.
    OpenUrlCrossRefPubMed
  82. 82.
    1. Peng J,
    2. Hu Q,
    3. Liu W,
    4. He X,
    5. Cui L,
    6. Chen X,
    7. et al.
    USP9X expression correlates with tumor progression and poor prognosis in esophageal squamous cell carcinoma. Diagn Pathol 2013;8:177.
    OpenUrlCrossRefPubMed
  83. 83.
    1. Sun H,
    2. Kapuria V,
    3. Peterson LF,
    4. Fang D,
    5. Bornmann WG,
    6. Bartholomeusz G,
    7. et al.
    Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood 2011;117:3151–62.
    OpenUrlAbstract/FREE Full Text
  84. 84.
    1. Deng S,
    2. Zhou H,
    3. Xiong R,
    4. Lu Y,
    5. Yan D,
    6. Xing T,
    7. et al.
    Over-expression of genes and proteins of ubiquitin specific peptidases (USPs) and proteasome subunits (PSs) in breast cancer tissue observed by the methods of RFDD-PCR and proteomics. Breast Cancer Res Treat 2007;104:21–30.
    OpenUrlCrossRefPubMed
  85. 85.
    1. Lin Z,
    2. Yang H,
    3. Tan C,
    4. Li J,
    5. Liu Z,
    6. Quan Q,
    7. et al.
    USP10 antagonizes c-Myc transcriptional activation through SIRT6 stabilization to suppress tumor formation. Cell Rep 2013;5:1639–49.
    OpenUrlCrossRefPubMed
  86. 86.
    1. Zeng Z,
    2. Wu HX,
    3. Zhan N,
    4. Huang YB,
    5. Wang ZS,
    6. Yang GF,
    7. et al.
    Prognostic significance of USP10 as a tumor-associated marker in gastric carcinoma. Tumour Biol 2014;35:3845–53.
    OpenUrlCrossRefPubMed
  87. 87.
    1. Harper S,
    2. Gratton HE,
    3. Cornaciu I,
    4. Oberer M,
    5. Scott DJ,
    6. Emsley J,
    7. et al.
    Structure and catalytic regulatory function of ubiquitin specific protease 11 N-terminal and ubiquitin-like domains. Biochem 2014;53:2966–78.
    OpenUrlCrossRefPubMed
  88. 88.
    1. Al-Salihi MA,
    2. Herhaus L,
    3. Macartney T,
    4. Sapkota GP
    . USP11 augments TGFbeta signalling by deubiquitylating ALK5. Open Biol 2012;2:120063.
    OpenUrlAbstract/FREE Full Text
  89. 89.
    1. Bayraktar S,
    2. Gutierrez Barrera AM,
    3. Liu D,
    4. Pusztai L,
    5. Litton J,
    6. Valero V,
    7. et al.
    USP-11 as a predictive and prognostic factor following neoadjuvant therapy in women with breast cancer. Cancer J 2013;19:10–7.
    OpenUrlCrossRefPubMed
  90. 90.
    1. Burkhart RA,
    2. Peng Y,
    3. Norris ZA,
    4. Tholey RM,
    5. Talbott VA,
    6. Liang Q,
    7. et al.
    Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival. Mol Cancer Res 2013;11:901–11.
    OpenUrlAbstract/FREE Full Text
  91. 91.
    1. de la Vega M,
    2. Kelvin AA,
    3. Dunican DJ,
    4. McFarlane C,
    5. Burrows JF,
    6. Jaworski J,
    7. et al.
    The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility. Nat Commun 2011;2:259.
    OpenUrlCrossRefPubMed
  92. 92.
    1. Hu M,
    2. Li P,
    3. Song L,
    4. Jeffrey PD,
    5. Chenova TA,
    6. Wilkinson KD,
    7. et al.
    Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO J 2005;24:3747–56.
    OpenUrlAbstract/FREE Full Text
  93. 93.
    1. Shinji S,
    2. Naito Z,
    3. Ishiwata S,
    4. Ishiwata T,
    5. Tanaka N,
    6. Furukawa K,
    7. et al.
    Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases. Oncol Rep 2006;15:539–43.
    OpenUrlPubMed
  94. 94.
    1. Wu N,
    2. Liu C,
    3. Bai C,
    4. Han YP,
    5. Cho WC,
    6. Li Q
    . Over-expression of deubiquitinating enzyme USP14 in lung adenocarcinoma promotes proliferation through the accumulation of beta-catenin. Int J Mol Sci 2013;14:10749–60.
    OpenUrlCrossRefPubMed
  95. 95.
    1. Elliott PR,
    2. Liu H,
    3. Pastok MW,
    4. Grossmann GJ,
    5. Rigden DJ,
    6. Clague MJ,
    7. et al.
    Structural variability of the ubiquitin specific protease DUSP-UBL double domains. FEBS Lett 2011;585:3385–90.
    OpenUrlCrossRefPubMed
  96. 96.
    1. Harper S,
    2. Besong TM,
    3. Emsley J,
    4. Scott DJ,
    5. Dreveny I
    . Structure of the USP15 N-terminal domains: a beta-hairpin mediates close association between the DUSP and UBL domains. Biochem 2011;50:7995–8004.
    OpenUrlCrossRefPubMed
  97. 97.
    1. de Jong RN,
    2. Ab E,
    3. Diercks T,
    4. Truffault V,
    5. Daniels M,
    6. Kaptein R,
    7. et al.
    Solution structure of the human ubiquitin-specific protease 15 DUSP domain. J Biol Chem 2006;281:5026–31.
    OpenUrlAbstract/FREE Full Text
  98. 98.
    1. Eichhorn PJ,
    2. Rodon L,
    3. Gonzalez-Junca A,
    4. Dirac A,
    5. Gili M,
    6. Martinez-Saez E,
    7. et al.
    USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma. Nat Med 2012;18:429–35.
    OpenUrlCrossRefPubMed
  99. 99.
    1. Inui M,
    2. Manfrin A,
    3. Mamidi A,
    4. Martello G,
    5. Morsut L,
    6. Soligo S,
    7. et al.
    USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol 2011;13:1368–75.
    OpenUrlCrossRefPubMed
  100. 100.
    1. Pai MT,
    2. Tzeng SR,
    3. Kovacs JJ,
    4. Keaton MA,
    5. Li SS,
    6. Yao TP,
    7. et al.
    Solution structure of the Ubp-M BUZ domain, a highly specific protein module that recognizes the C-terminal tail of free ubiquitin. J Mol Biol 2007;370:290–302.
    OpenUrlCrossRefPubMed
  101. 101.
    1. Ye Y,
    2. Akutsu M,
    3. Reyes-Turcu F,
    4. Enchev RI,
    5. Wilkinson KD,
    6. Komander D
    . Polyubiquitin binding and cross-reactivity in the USP domain deubiquitinase USP21. EMBO Rep 2011;12:350–7.
    OpenUrlAbstract/FREE Full Text
  102. 102.
    1. McFarlane C,
    2. Kelvin AA,
    3. de la Vega M,
    4. Govender U,
    5. Scott CJ,
    6. Burrows JF,
    7. et al.
    The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1–S progression. Cancer Res 2010;70:3329–39.
    OpenUrlAbstract/FREE Full Text
  103. 103.
    1. McFarlane C,
    2. McFarlane S,
    3. Paul I,
    4. Arthur K,
    5. Scheaff M,
    6. Kerr K,
    7. et al.
    The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis. Oncotarget 2013;4:1836–43.
    OpenUrlPubMed
  104. 104.
    1. Yan M,
    2. Luo JK,
    3. Ritchie KJ,
    4. Sakai I,
    5. Takeuchi K,
    6. Ren R,
    7. et al.
    Ubp43 regulates BCR-ABL leukemogenesis via the type 1 interferon receptor signaling. Blood 2007;110:305–12.
    OpenUrlAbstract/FREE Full Text
  105. 105.
    1. Hassink GC,
    2. Zhao B,
    3. Sompallae R,
    4. Altun M,
    5. Gastaldello S,
    6. Zinin NV,
    7. et al.
    The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep 2009;10:755–61.
    OpenUrlAbstract/FREE Full Text
  106. 106.
    1. Lee JG,
    2. Kim W,
    3. Gygi S,
    4. Ye Y
    . Characterization of the deubiquitinating activity of USP19 and its role in endoplasmic reticulum-associated degradation. J Biol Chem 2014;289:3510–7.
    OpenUrlAbstract/FREE Full Text
  107. 107.
    1. Li Z,
    2. Wang D,
    3. Na X,
    4. Schoen SR,
    5. Messing EM,
    6. Wu G
    . Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor. Biochem Biophys Res Commun 2002;294:700–9.
    OpenUrlCrossRefPubMed
  108. 108.
    1. Yasunaga J,
    2. Lin FC,
    3. Lu X,
    4. Jeang KT
    . Ubiquitin-specific peptidase 20 targets TRAF6 and human T cell leukemia virus type 1 tax to negatively regulate NF-kappaB signaling. J Virol 2011;85:6212–9.
    OpenUrlAbstract/FREE Full Text
  109. 109.
    1. Riester M,
    2. Werner L,
    3. Bellmunt J,
    4. Selvarajah S,
    5. Guancial EA,
    6. Weir BA,
    7. et al.
    Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma. Clin Cancer Res 2014;20:1873–83.
    OpenUrlAbstract/FREE Full Text
  110. 110.
    1. Xu G,
    2. Tan X,
    3. Wang H,
    4. Sun W,
    5. Shi Y,
    6. Burlingame S,
    7. et al.
    Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1. J Biol Chem 2010;285:969–78.
    OpenUrlAbstract/FREE Full Text
  111. 111.
    1. Dai W,
    2. Yao Y,
    3. Zhou Q,
    4. Sun CF
    . Ubiquitin-specific peptidase 22, a histone deubiquitinating enzyme, is a novel poor prognostic factor for salivary adenoid cystic carcinoma. PLoS ONE 2014;9:e87148.
    OpenUrlCrossRefPubMed
  112. 112.
    1. Liang J,
    2. Zhang X,
    3. Xie S,
    4. Zhou X,
    5. Shi Q,
    6. Hu J,
    7. et al.
    Ubiquitin-specific protease 22: a novel molecular biomarker in glioma prognosis and therapeutics. Med Oncol 2014;31:899.
    OpenUrlCrossRefPubMed
  113. 113.
    1. Ning J,
    2. Zhang J,
    3. Liu W,
    4. Lang Y,
    5. Xue Y,
    6. Xu S
    . Overexpression of ubiquitin-specific protease 22 predicts poor survival in patients with early-stage non–small cell lung cancer. Eur J Histochem 2012;56:e46.
    OpenUrlCrossRefPubMed
  114. 114.
    1. Piao S,
    2. Ma J,
    3. Wang W,
    4. Liu Y,
    5. Zhang M,
    6. Chen H,
    7. et al.
    Increased expression of USP22 is associated with disease progression and patient prognosis of salivary duct carcinoma. Oral Oncol 2013;49:796–801.
    OpenUrlCrossRefPubMed
  115. 115.
    1. Schrecengost RS,
    2. Dean JL,
    3. Goodwin JF,
    4. Schiewer MJ,
    5. Urban MW,
    6. Stanek TJ,
    7. et al.
    USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Res 2014;74:272–86.
    OpenUrlAbstract/FREE Full Text
  116. 116.
    1. Wang H,
    2. Li YP,
    3. Chen JH,
    4. Yuan SF,
    5. Wang L,
    6. Zhang JL,
    7. et al.
    Prognostic significance of USP22 as an oncogene in papillary thyroid carcinoma. Tumour Biol 2013;34:1635–9.
    OpenUrlCrossRefPubMed
  117. 117.
    1. Blount JR,
    2. Burr AA,
    3. Denuc A,
    4. Marfany G,
    5. Todi SV
    . Ubiquitin-specific protease 25 functions in Endoplasmic Reticulum-associated degradation. PLoS ONE 2012;7:e36542.
    OpenUrlCrossRefPubMed
  118. 118.
    1. Zhong B,
    2. Liu X,
    3. Wang X,
    4. Liu X,
    5. Li H,
    6. Darnay BG,
    7. et al.
    Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3. Sci Signal 2013;6:ra35.
    OpenUrlAbstract/FREE Full Text
  119. 119.
    1. Liu J,
    2. Chung HJ,
    3. Vogt M,
    4. Jin Y,
    5. Malide D,
    6. He L,
    7. et al.
    JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. EMBO J 2011;30:846–58.
    OpenUrlAbstract/FREE Full Text
  120. 120.
    1. Martin Y,
    2. Cabrera E,
    3. Amoedo H,
    4. Hernandez-Perez S,
    5. Dominguez-Kelly R,
    6. Freire R
    . USP29 controls the stability of checkpoint adaptor Claspin by deubiquitination. Oncogene. 2014 Mar 17. [Epub ahead of print].
  121. 121.
    1. Akhavantabasi S,
    2. Akman HB,
    3. Sapmaz A,
    4. Keller J,
    5. Petty EM,
    6. Erson AE
    . USP32 is an active, membrane-bound ubiquitin protease overexpressed in breast cancers. Mamm Genome 2010;21:388–97.
    OpenUrlCrossRefPubMed
  122. 122.
    1. Schulte I,
    2. Batty EM,
    3. Pole JC,
    4. Blood KA,
    5. Mo S,
    6. Cooke SL,
    7. et al.
    Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes. BMC Genomics 2012;13:719.
    OpenUrlCrossRefPubMed
  123. 123.
    1. Allen MD,
    2. Bycroft M
    . The solution structure of the ZnF UBP domain of USP33/VDU1. Protein Sci 2007;16:2072–5.
    OpenUrlCrossRefPubMed
  124. 124.
    1. Li Z,
    2. Na X,
    3. Wang D,
    4. Schoen SR,
    5. Messing EM,
    6. Wu G
    . Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. J Biol Chem 2002;277:4656–62.
    OpenUrlAbstract/FREE Full Text
  125. 125.
    1. Paulsson K,
    2. Bekassy AN,
    3. Olofsson T,
    4. Mitelman F,
    5. Johansson B,
    6. Panagopoulos I
    . A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42. Leukemia 2006;20:224–9.
    OpenUrlCrossRefPubMed
  126. 126.
    1. Aressy B,
    2. Jullien D,
    3. Cazales M,
    4. Marcellin M,
    5. Bugler B,
    6. Burlet-Schiltz O,
    7. et al.
    A screen for deubiquitinating enzymes involved in the G(2)/M checkpoint identifies USP50 as a regulator of HSP90-dependent Wee1 stability. Cell Cycle 2010;9:3815–22.
    OpenUrlCrossRefPubMed
  127. 127.
    1. Delgado-Diaz MR,
    2. Martin Y,
    3. Berg A,
    4. Freire R,
    5. Smits VA
    . Dub3 controls DNA damage signalling by direct deubiquitination of H2AX. Mol Oncol 2014;8:884–93.
    OpenUrlCrossRefPubMed
  128. 128.
    1. Pereg Y,
    2. Liu BY,
    3. O'Rourke KM,
    4. Sagolla M,
    5. Dey A,
    6. Komuves L,
    7. et al.
    Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. Nat Cell Biol 2010;12:400–6.
    OpenUrlCrossRefPubMed
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Cancer Research: 74 (18)
September 2014
Volume 74, Issue 18

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Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer
Anupama Pal, Matthew A. Young and Nicholas J. Donato
Cancer Res September 15 2014 (74) (18) 4955-4966; DOI: 10.1158/0008-5472.CAN-14-1211
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