BMB Reports 2019; 52(3): 181-189  https://doi.org/10.5483/BMBRep.2019.52.3.048
Deubiquitinating enzymes as cancer biomarkers: new therapeutic opportunities?
Naresh Poondla1,#, Arun Pandian Chandrasekaran1,#, Kye-Seong Kim1,2,*, and Suresh Ramakrishna1,2,*
1Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, 2College of Medicine, Hanyang University, Seoul 04763, Korea
Correspondence to: *Suresh Ramakrishna, Tel: +82-2-2220-2424; Fax: +82-2-2220-2422; E-mail: suri28@hanyang.ac.kr, suresh.ramakris@gmail.com; Kye-Seong Kim, Tel: +82-2-2220-0607; Fax: +82-2-2220-2422; E-mail: ks66kim@hanyang.ac.kr
#These authors contributed equally to this work.
Received: January 10, 2019; Published online: March 31, 2019.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Cancer remains a life-threatening disease and accounts for the major mortality rates worldwide. The practice of using biomarkers for early detection, staging, and customized therapy may increase cancer patients’ survival. Deubiquitinating enzymes (DUBs) are a family of proteases that remove ubiquitin tags from proteins of interest undergoing proteasomal degradation. DUBs play several functional roles other than deubiquitination. One of the important roles of DUBs is regulation of tumor progression. Several reports have suggested that the DUB family members were highly-elevated in various cancer cells and tissues in different stages of cancer. These findings suggest that the DUBs could be used as drug targets in cancer therapeutics. In this review, we recapitulate the role of the DUB family members, including ubiquitin-specific protease, otubain protease, and important candidates from other family members. Our aim was to better understand the connection between DUB expression profiles and cancers to allow researchers to design inhibitors or gene therapies to improve diagnosis and prognosis of cancers.

Keywords: Cancer, Deubiquitinating enzymes, Gene therapy, Inhibitors, Otubain protease, Ubiquitin-specific protease
INTRODUCTION

Cancer is one of the major diseases causing death globally, accounting for 8.2 million deaths in 2012 (1). Recent advances in molecular and cellular biology have played important roles in understanding cancer and breakthroughs that have been being translated into therapy. Because of these recent developments, genes that are involved in cancer are being unraveled (2, 3). Most of the known cancer genes were originally identified by genetic evidence. A protein that is encoded by a cancer gene typically regulates cell proliferation and differentiation and eventually leads to cell death or apoptosis. Mutations that lead to oncogenesis typically occur in genes that mediate DNA repair mechanisms (4).

Ubiquitin proteasome pathway

The post-translational attachment of ubiquitin is a modification that can determine a protein’s fate. While ubiquitin itself is a small conserved protein, its covalent conjugation to protein substrates and to other ubiquitin molecules is a tightly-controlled process involving complex cellular machinery. Perhaps the most prominent and well-known function of ubiquitin is to target a protein for degradation by the 26S proteasome. Degradation can be accomplished via an isopeptide bond formation between the carboxy-terminal glycine (Gly) site on the ubiquitin and an ɛ-amino group of the lysine (Lys) side chains of a protein substrate. The ubiquitin-substrate system is further diversified via the process of polyubiquitination, during which a ubiquitin molecule’s C-terminal Gly is conjugated with one of the seven Lys residues on another ubiquitin (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, or Lys63) or with the N-terminus to form linear chains.

The ubiquitin-proteasome protein degradation pathway is comprised of ubiquitin, a three-enzyme ubiquitination complex, the intracellular protein ubiquitination targets, and the proteasome that is the organelle of protein degradation, as well as ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3).

Deubiquitinating enzymes

Deubiquitinating enzymes (DUBs) are proteases that reverse protein ubiquitination, a process which is significant for normal homeostasis. DUBs have four distinct mechanisms of action: 1) processing of ubiquitin precursors, 2) recycling of ubiquitin molecules during ubiquitination, 3) cleavage of polyubiquitin chains, and 4) reversal of ubiquitin conjugation (Fig. 1). DUBs regulate several cellular functions, including proteasome-dependent and lysosome-dependent proteolysis, gene expression, cell cycle progression, chromosome segregation, kinase activation, apoptosis, localization, DNA repair, maintenance of stemness, spermatogenesis, and degradation of signaling intermediates (510).

Approximately 100 DUBs are encoded in the human genome (10). Based on the organization of the catalytic domain, DUBs are classified into distinct families, the vast majority of which are cysteine proteases. These include ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor proteases (OTUs), Machado-Joseph disease proteases (MJDs), Jab1/Mov34/Mpr1 (JAMM) metalloproteases, and the recently-discovered MIU-containing novel DUB family, (MINDY) proteases (11).

UBIQUITIN-SPECIFIC PROTEASE FAMILY

USP2

USP2a, an isoform of USP2, is an androgen-regulated DUB that deubiquitinates the antiapoptotic proteins such as fatty acid synthase, Mdm2, and MdmX (12). USP2a expression is increased in glioma cells compared to normal brain tissues, which suggests that USP2a may correlate with malignant glioma progression, and therefore may be an effective marker for glioma prognosis (13). Furthermore, USP2 plays a role in tumor metastasis by modulating the activity or expression of MMP2, suggesting its use as a potential breast cancer marker (13).

USP4

USP4 has been strongly implicated in the regulation of tumor metastasis in breast cancer (14), liver cancer (15), and colorectal cancer (16). USP4 is significantly increased in melanoma and plays an oncogenic role by simultaneously inhibiting stress-induced cell apoptosis and promoting tumor metastasis (17). USP4 is an important protein that facilitates hepatocellular carcinoma (HCC) progression by stabilizing CYPA through deubiquitination and activating MAPK/CrkII signaling pathways, indicating that USP4 may act as a novel marker to predict prognosis and present a therapeutic opportunity for HCC (18). In breast cancer, USP4 promotes the migration and invasion of breast cancer cells via RLX-mediated TGF-β/Smad2/MMP-9 pathways, providing an attractive target for breast cancer therapy (19). The above results suggested that overexpression of USP4 in various cancers is due to the stabilization of other oncogenes in the respective cancer types. Thus, targeting USP4 as a biomarker could be useful for the early diagnosis of cancer.

USP5

USP5 acts as a exopeptidase that hydrolyzes isopeptide bonds in poly-ubiquitin from their free carboxy-terminal ends to produce monoubiquitin (20). USP5 knockdown suppressed cell proliferation, migration, and drug resistance and induced apoptosis, while USP5 overexpression promoted colony formation, migration, drug resistance, and tumorigenesis (21). USP5 plays a critical role in hepatocarcinogenesis through inactivation of the p14–p53 signaling pathway contributing to tumorigenesis and drug resistance, which provides a clue that USP5 could be a potential therapeutic target for HCC (22). In pancreatic cancer, USP5 plays a critical role in tumorigenesis and progression by stabilizing the FoxM1 protein, showing therapeutic potential against pancreatic cancer (23).

USP7

USP7, also known as herpes-associated ubiquitin-specific protease (HAUSP), was originally identified as an ubiquitin-specific protease that binds to a viral-encoded protein, called Vmw110 (24). HAUSP protein can bind to the herpes simplex virus type 1 (HSV-1) regulatory protein, which is known as infected cell polypeptide (ICPO). In epithelial ovarian cancer (EOC), USP7 and MARCH7 proteins are differentially expressed and the combination of USP7 and MARCH7 expression may function as promising biomarkers for EOC prognosis (25). HCC is one of the most dominant cancer types in the world. High expression of USP7 mRNA and protein levels in HCC tissues compared to normal liver samples has been reported (26). Cell-based assays have suggested that USP7 expression confers cell proliferation, migration, and invasion capabilities. These data suggest that USP7 could be a novel independent prognostic marker for HCC. Recently, a study suggested that USP7 deubiquitinates Ki-67, and thereby promotes cell proliferation in non-small-cell lung cancer (NSCLC) (27). Here, both Ki-67 and USP7 were expressed in NSCLC cells. Statistical data revealed a strong correlation between USP7 and Ki-67 levels. In contrast, siRNA targeting USP7 increased the ubiquitination of Ki-67 and led to delayed tumor growth. The above evidence suggests that USP7 could be an important therapeutic target in various cancer types.

USP8

USP8 belongs to the USP superfamily of DUBs targeting several substrates (28), including smoothened (29), frizzled (30), neuregulin receptor degradation protein-1, and receptor tyrosine kinase. Recently, the expression profile of USP8 in cervical squamous cell carcinoma (CSCC) has been studied (31). USP8 was upregulated in CSCC tissue samples compared to non-cancerous cervical tissues. Also, high expression of USP8 was associated with tumor stage and was recognized as an independent prognostic marker for CSCC. Elevated levels of USP8 led to cell proliferation, migration, and invasion of CSCC cell lines. Thus, USP8 could be a therapeutic and diagnostic target in CSCC patients.

USP10

USP10, also known as UBPO, is a protein consisting of 798 amino acids and was originally discovered as a DUB that interacts with the Ras-GAP SH3 domain-binding protein (32). Increased USP10 expression has been detected in some breast cancer and glioblastoma samples. Overexpression of USP10 has been associated with poor prognosis for glioblastoma multiforme patients, while decreased USP10 has been observed in gastric cancer tissues, and its downregulation has been associated with invasion, metastasis, and poor prognosis of gastric cancer. Current studies have also shown that USP10 suppressed proliferation and growth of pancreatic cancer cells. Therefore, USP10, as a novel DUB, has a crucial role in various pathological processes of tumors. In gastric cancer (GC), clinical samples and cell lines showed low-level expression of USP10, and negative USP10 expression was associated with a marked propensity toward gastric wall invasion, lymph node metastasis, highly malignant biological behavior, and poor survival. USP10 identification in GC can potentially serve as a new prognostic indicator predicting the treatment outcome for GC patients.

USP22

USP22 is a novel DUB that has been related to cell cycle progression, therapy resistance, and metastasis. The expression frequency of USP22 was extremely high in HCC compared to normal liver tissues (31). Elevated levels of USP22 represented poor HCC patient survival and have also been associated with greater mortality in patients with advanced tumor stages, shown by Kaplan-Meier analysis. As revealed by multivariate analyses, USP22 is a self-regulating prognostic marker in HCC. Several other researchers have reported that USP22 was overexpressed in salivary duct carcinoma (33) and esophageal squamous cell carcinoma (34). The above findings indicate that high USP22 expression might be an important factor in tumor progression and may serve as an independent molecular marker.

USP32

USP32 is a highly-conserved and uncharacterized gene, located on the 17q23.1–17q23.2 chromosomal band (35). USP32 was present in 22% of primary breast cancer tumors compared to non-cancerous mammary tissues, and 50% of breast cancer cell lines. Endogenously, USP32 was highly-elevated in the MCF7 cell line, and no mutation was detected in this cell line, indicating that the wild-type gene was overexpressed. Additionally, USP32 has a role in human small cell lung cancer (SCLC) (36). USP32 is highly-expressed in SCLC tissue samples compared to normal tissues. During the disease aggravation stage, USP32 has been positively correlated with SCLC expression. On the other hand, downregulation of USP32 in vitro caused reduced migration and proliferation rates of SCLC cells. Also, this downregulation arrested the cells at the G0/G1 phase by elevating p21 and decreasing CDK4-cyclin D1 complex levels. Cleaved caspase-3 and cleaved-PARP were activated when the USP32 gene was silenced, eventually leading to apoptosis by altering the epithelial-mesenchymal transition. Overall, USP32 could be a potential target for breast and lung cancers.

OTUBAIN PROTEASE FAMILY

OTUB1

The OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) belongs to the OTU DUB family and is reported to be involved in various malignancies (3740). Recently, the role of OTUB1 in human gliomas has been elucidated (41). Immunoblot and immunohistochemical experiments validated that glioma tissues overexpress OTUB1 genes and statistical studies showed that the expression pattern of OTUB1 was highly-linked to the WHO grades of the gliomas. On the other hand, downregulation of OTUB1 was linked to poor migration and also elevated EMT-related protein E-cadherin expression. Thus, OTUB1 might be involved in the regulation of ECM stability. The above results suggested that OTUB1 could be an important cancer marker in gliomas and other malignancies and could be a potential target for successful cancer therapy.

A20

A20 is a DUB that was originally found to be involved in autoimmunity and inflammation (42). However, a recent study proposed that A20 is highly involved in cancer metastasis (43). Here, A20 overexpression leads to metastasis of basal-like breast cancer by monoubiquitinating Snail1. In human basal-like breast cancers, A20 was significantly overexpressed and accounted for cancer metastasis. Additionally, A20 mediates TGF-β1-induced EMT of breast cancers by monoubiquitylating Snail1. Reports also suggested that the transient knockdown of A20 displayed decreased lung cancer metastasis in orthotopic breast cancer models and mouse xenografts.

DUB INHIBITORS

A number of reports have described the identification and utility of small molecule DUB inhibitors as anticancer agents (44). Inhibition of DUBs leads to cellular changes, such as (i) aggregation of polyubiquitinated protein molecules, (ii) reduction in the group of monomeric ubiquitin moieties, (iii) increased rates of polyubiquitin assembly, (iv) overall reduction in DUB events, and (v) altered cellular activities, such as DUB regulation of oncoproteins (45). Generally, DUB inhibition leads to impaired proteasome function and aggregation of misfolded functional proteins, resulting in cellular toxicity and death. DUBs that control oncogenic proteins can be targeted by small molecules that inhibit deubiquitinating activity via UPS degradation, while DUBs that control tumor suppressors can be targeted by increasing the deubiquitinating activity, thus inhibiting oncogenic progression. Several studies have been carried out to design small molecule DUB inhibitors because they are simpler to design than enzyme activators, using substrate modeling and competitive inhibition (46, 47). A schematic representation of DUB inhibition on relevant pathways is depicted in Fig. 2.

An extensive study was carried out to discover drugs that inhibit DUBs and resulted in the discovery of ubiquitin aldehyde (Ubal) and ubiquitin vinyl sulfone (UbVS) (48). Due to their high molecular weights, peptidic nature, and lack of specificity, these compounds were not pharmacologically sustainable (48). The UCH family of proteins is involved in deubiquitination by removing ubiquitin from C-terminal adducts (48). Hence, researchers have made an effort to design their inhibitors and ended up with an isatin O-acyl oximes series (48). They are competitive and capable of directly targeting the active site with minimal IC50 values. Basically, UCH-L1 decreases cell proliferation in neuroblastoma cells; when this inhibitor is applied, cell proliferation is elevated. Thus, the data support the anti-proliferative nature of UCH-L1 proteins. A novel proteasome-inhibitory compound has been synthesized, called b-AP15 (49). The b-AP15 small molecule specifically inhibits USP14 and UCHL5 which are associated with 19S RP. Additionally, the compound b-AP15 showed effective anti-cancer responses against other refractory cancer types. Inhibitors targeting other important DUBs are described in Table 1.

CONCLUSION

This review delivers a comprehensive report of the DUBs for cancer diagnosis and prognosis. Recent developments of cancer therapies and the promptness of their application to clinical use for various tumors validate the prospects of exploiting DUBs as targets for drug development. The expression profiles of several DUBs in different cancer types are discussed in Table 2. Moreover, these DUBs exert their function through binding to their proteins, which can be targeted. In other cases, the DUB itself seems to be an excellent drug target. More detailed information on the roles, localization, regulation, and substrates of DUBs will help researchers understand their roles in oncogenesis and clinical applications of their inhibitors. Enhanced improvement in small molecule pharmacological development against DUBs will permit greater success in the treatment of cancer and other deadly diseases.

ACKNOWLEDGEMENTS

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2017R 1A2B2008727, 2018M3A9H3022412 and 2017M3A9B3061830) and Bio and Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government (MSIP and MOHW) (2017M3A9E4048172).

Figures
Fig. 1. Various catalytic mechanisms exhibited by DUBs. DUBs can unknot ubiquitin conjugation by cleaving the bond between ubiquitin molecules and ubiquitin-target complexes, editing ubiquitin chains to remove one or more ubiquitin molecules, and finally, recycling of ubiquitin molecules in the ubiquitin-proteasome pathway.
Fig. 2. DUBs involved in the regulation of oncogenic pathways. Inhibition of specific DUBs leads to decreased cancer proliferation, drug resistance, and delayed metastasis.
Tables

DUBs and their inhibitors in cancer therapeutics

DUB Inhibitor(s) Disease Indication Stage of development References
USP1 ML323, Pimozide Oncology Preclinical (50)
USP2 ML364 Inflammation Preclinical (50)
USP4 Vialinin A Inflammation and oncology Preclinical (51, 52)
USP5 WP1130
USP7 ADC-01, ADC-03 Oncology, Immuno-oncology Preclinical (53)
HBX41108 Oncology, Immuno-oncology Preclinical (54, 55)
P5091 Oncology, Immuno-oncology Preclinical (56)
P22077 Oncology, Immuno-oncology Preclinical (56)
USP8 9-(Ethoxyimino)-9H-indeno (1,2-b) pyra-zine-2,3-dicarbonitrile Oncology Preclinical (56)
USP9X WP1130 Oncology Preclinical (57)
USP10 and USP13 Spautin 1 Inflammation Preclinical (57)
USP11 Mitoxantrone Oncology Preclinical (58)
USP14 1U1, b-AP15, VLX1570, wp1130 Neurodegeneration Preclinical (59)
USP20 GSK2643943A Oncology Preclinical (60)
USP30 15-oxospiramilactone Neurodegeneration Preclinical (61)
USP47 P5091 Cancer Preclinical (56)
UCH37 WP1130 Cancer Preclinical (57)
UCHL5 b-AP15 Neurology Preclinical (62)
UCHL1 LDN-57444 Cancer Preclinical (63)
UCHL3 LDN-57444 Cancer Preclinical (64)
UCHL5 TCID, b-AP15 Cancer Preclinical (62, 65)
UCH37 WP1130 Cancer Preclinical (57)

DUBs expressed in various types of cancer

Disease DUB References
Gliomas USP2a, USP22, USP44, BAP1, OTUB1 (41, 66, 67)
Breast cancer USP2, USP22, USP37 (68, 69)
Hepatocellular carcinoma USP4, USP5, USP11, USP22, UCHL1, A20, OTUB1 (70, 71)
Esophageal cancer USP4 (72)
Melanoma USP4 (72)
Pancreatic cancer USP5 (72)
Epithelial ovarian cancer USP7 (72)
Lung adenocarcinoma USP8 (73, 74)
Gastric carcinoma USP10 (75)
Endometrial cancer USP14 (75)
Non-small cell lung carcinoma USP17, USP22, OTUD7B, OTUD6B (76, 77)
Renal clear cell carcinoma USP21 (78)
Muscle invasive bladder cancer USP18 (79)
Cervical cancer USP22 (80)
Oral squamous cell carcinoma USP22 (81)
Papillary thyroid carcinoma USP22, USP33 (82, 83)
Salivary duct carcinoma USP22 (33)
Esophageal squamous cell carcinoma USP22 (34)
Salivary adenoid cystic carcinoma USP22 (34)
Bladder cancer USP28 (84)
Colorectal cancer USP33, OTUB1, MYSM1 (85, 86)
Prostate cancer USP39 (87)
Malignant peritoneal mesothelioma BAP1 (88)
Triple-negative breast cancer OTUD7B (89)
Pancreatic ductal adenocarcinoma UCHL5 (90)
Gastric cardiac adenocarcinoma UCHL1 (91)
Cholangiocarcinoma UCHL1 (91)
Aggressive multiple myeloma UCHL1 (92)
Neuronal apoptosis USP4, UCHL1 (93, 94)
Cardiac hypertrophy USP4 (95)
Aneurysmal bone cyst USP6 (96)
Pancreatic beta cells UCHL1 (97)
Aneurysmal subarachnoid hemorrhage UCHL1 (98)
Neuronal biomarker UCHL1 (98)
Traumatic brain injury UCHL1 (99)
Pancreatic neuroendocrine tumors UCHL1 (100)

References
  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, and Jemal A (2012) Global cancer statistics. CA Cancer J Clin 65, 87-108.
    Pubmed CrossRef
  2. Li J, Shen H, and Himmel KL (1999) Leukaemia disease genes: large-scale cloning and pathway predictions. Nat Genet 23, 348-353.
    Pubmed CrossRef
  3. Hansen GM, Skapura D, and Justice MJ (2000) Genetic profile of insertion mutations in mouse leukemias and lymphomas. Genome Res 10, 237-243.
    Pubmed KoreaMed CrossRef
  4. Fishel R, Lescoe MK, and Rao MR (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027-1038.
    Pubmed CrossRef
  5. Sharma A, Alswillah T, and Singh K (2018) USP14 regulates DNA damage repair by targeting RNF168-dependent ubiquitination. Autophagy 14, 1976-1990.
    Pubmed KoreaMed CrossRef
  6. Chandrasekaran AP, Suresh B, Kim HH, Kim K-S, and Ramakrishna S (2017) Concise Review: Fate Determination of Stem Cells by Deubiquitinating Enzymes. Stem Cells 35, 9-16.
    Pubmed CrossRef
  7. Lork M, Verhelst K, and Beyaert R (2017) CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell Death Differ 24, 1172-1183.
    Pubmed KoreaMed CrossRef
  8. Darling S, Fielding AB, Sabat-Pośpiech D, Prior IA, and Coulson JM (2017) Regulation of the cell cycle and centrosome biology by deubiquitylases. Biochem Soc Trans 45, 1125-1136.
    Pubmed KoreaMed CrossRef
  9. Jacq X, Kemp M, Martin NMB, and Jackson SP (2013) Deubiquitylating Enzymes and DNA Damage Response Pathways. Cell Biochem Biophys 67, 25-43.
    Pubmed KoreaMed CrossRef
  10. Nijman SMB, Luna-Vargas MPA, and Velds A (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773-786.
    Pubmed CrossRef
  11. Abdul Rehman SA, Kristariyanto YA, and Choi SY (2016) MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes. Mol Cell 63, 146-155.
    Pubmed KoreaMed CrossRef
  12. Priolo C, Tang D, and Brahamandan M (2006) The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Res 66, 8625-8632.
    Pubmed CrossRef
  13. Qu Q, Mao Y, and Xiao G (2015) USP2 promotes cell migration and invasion in triple negative breast cancer cell lines. Tumor Biol 36, 5415-5423.
    Pubmed CrossRef
  14. Zhang L, Zhou F, and Drabsch Y (2012) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type i receptor. Nat Cell Biol 14, 717-726.
    Pubmed CrossRef
  15. Seibold MA, and Schwartz DA (2011) The authors reply. N Engl J Med 364, 1503-1512.
    Pubmed KoreaMed CrossRef
  16. Xing C, Lu XX, and Da Guo P (2016) Ubiquitin-specific protease 4-mediated deubiquitination and stabilization of PRL-3 is required for potentiating colorectal oncogenesis. Cancer Res 76, 83-95.
    Pubmed CrossRef
  17. Guo W, Ma J, and Pei T (2018) Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma. J Cell Mol Med 22, 2944-2954.
    Pubmed KoreaMed CrossRef
  18. Li T, Yan B, and Ma Y (2018) Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination. Cell Death Dis 9, 148-165.
    Pubmed KoreaMed CrossRef
  19. Cao WH, Liu XP, and Meng SL (2016) USP4 promotes invasion of breast cancer cells via Relaxin/TGF-β1/Smad2/MMP-9 signal. Eur Rev Med Pharmacol Sci 20, 1115-1122.
    Pubmed
  20. Hicke L (2001) Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2, 195-201.
    Pubmed CrossRef
  21. Tang B, Tang F, and Li B (2015) High USP22 expression indicates poor prognosis in hepatocellular carcinoma. Oncotarget 6, 12654-12667.
    Pubmed KoreaMed CrossRef
  22. Liu Y, Wang W, and Lu Y (2017) Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma 8, 50655-50664.
    Pubmed KoreaMed CrossRef
  23. Li XY, Wu HY, Mao XF, Jiang LX, and Wang YX (2017) USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein. Biochem Biophys Res Commun 492, 48-54.
    Pubmed CrossRef
  24. Cheon KW, and Baek KH (2006) HAUSP as a therapeutic target for hematopoietic tumors (Review). Int J Oncol 28, 1209-1215.
    Pubmed
  25. Zhang L, Wang H, Tian L, and Li H (2016) Expression of USP7 and MARCH7 Is Correlated with Poor Prognosis in Epithelial Ovarian Cancer. Tohoku J Exp Med 239, 165-175.
    Pubmed CrossRef
  26. Wang X, Zhang Q, Wang Y, Zhuang H, and Chen B (2018) Clinical Significance of Ubiquitin Specific Protease 7 (USP7) in Predicting Prognosis of Hepatocellular Carcinoma and its Functional Mechanisms. Med Sci Monit 24, 1742-1750.
    Pubmed KoreaMed CrossRef
  27. Zhang C, Lu J, and Zhang Q-W (2016) USP7 promotes cell proliferation through the stabilization of Ki-67 protein in non-small cell lung cancer cells. Int J Biochem Cell Biol 79, 209-221.
    Pubmed CrossRef
  28. Fraile JM, Quesada V, Rodríguez D, Freije JMP, and López-Otín C (2012) Deubiquitinases in cancer: New functions and therapeutic options. Oncogene 31, 2373-2388.
    Pubmed CrossRef
  29. Xia R, Jia H, Fan J, Liu Y, and Jia J (2012) USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS Biol 10, e1001238.
    Pubmed KoreaMed CrossRef
  30. Mukai A, Yamamoto-Hino M, Awano W, Watanabe W, Komada M, and Goto S (2010) Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt. EMBO J 29, 2114-2225.
    Pubmed KoreaMed CrossRef
  31. Yan M, Zhao C, Wei N, Wu X, Cui J, and Xing Y (2018) High Expression of Ubiquitin-Specific Protease 8 (USP8) Is Associated with Poor Prognosis in Patients with Cervical Squamous Cell Carcinoma. Med Sci Monit 24, 4934-4943.
    Pubmed KoreaMed CrossRef
  32. Soncini C, Berdo I, and Draetta G (2001) Ras-GAP SH3 domain binding protein (G3BP) is a modulator of USP10. Oncogene 20, 3869-3879.
    Pubmed CrossRef
  33. Piao S, Ma J, and Wang W (2013) Increased expression of USP22 is associated with disease progression and patient prognosis of salivary duct carcinoma. Oral Oncol 49, 796-801.
    Pubmed CrossRef
  34. Li J, Wang Z, and Li Y (2012) USP22 nuclear expression is significantly associated with progression and unfavorable clinical outcome in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 138, 1291-1297.
    Pubmed CrossRef
  35. Akhavantabasi S, Akman HB, Sapmaz A, Keller J, Petty EM, and Erson AE (2010) USP32 is an active, membrane-bound ubiquitin protease overexpressed in breast cancers. Mamm Genome 21, 388-397.
    Pubmed CrossRef
  36. Hu W, Wei H, Li K, Li P, Lin J, and Feng R (2017) Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer. Cell Prolif 50, e12343.
    Pubmed CrossRef
  37. Baietti MF, Simicek M, and Abbasi Asbagh L (2016) OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination. EMBO Mol Med 8, 288-303.
    Pubmed KoreaMed CrossRef
  38. Stanišić V, Malovannaya A, Qin J, Lonard DM, and O’Malley BW (2009) OTU Domain-containing Ubiquitin Aldehyde-binding Protein 1 (OTUB1) Deubiquitinates Estrogen Receptor (ER) α and Affects ERα Transcriptional Activity. J Biol Chem 284, 16135-16145.
    Pubmed KoreaMed CrossRef
  39. Zhang Y, Hu R, and Wu H (2012) OTUB1 Overexpression in Mesangial Cells Is a Novel Regulator in the Pathogenesis of Glomerulonephritis through the Decrease of DCN Level. PLoS One 7, e29654.
    Pubmed KoreaMed CrossRef
  40. Weng W, Zhang Q, and Xu M (2016) OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma. Am J Transl Res 8, 2234-2244.
    Pubmed KoreaMed
  41. Xu L, Li J, and Bao Z (2017) Silencing of OTUB1 inhibits migration of human glioma cells in vitro. Neuropathology 37, 217-226.
    Pubmed CrossRef
  42. Catrysse L, Vereecke L, Beyaert R, and van Loo G (2014) A20 in inflammation and autoimmunity. Trends Immunol 35, 22-31.
    Pubmed CrossRef
  43. Lee JH, Jung SM, and Yang KM (2017) A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1. Nat Cell Biol 19, 1260-1273.
    Pubmed CrossRef
  44. Ndubaku C, and Tsui V (2015) Inhibiting the deubiquitinating enzymes (DUBs). J Med Chem 58, 1581-1595.
    Pubmed CrossRef
  45. D’Arcy P, Wang X, and Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147, 32-54.
    Pubmed CrossRef
  46. Kaushal K, Antao AM, Kim KS, and Ramakrishna S (2018) Deubiquitinating enzymes in cancer stem cells: functions and targeted inhibition for cancer therapy. Drug Discov Today 23, 1974-1982.
    Pubmed CrossRef
  47. Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37, 937-953.
    Pubmed CrossRef
  48. Love KR, Catic A, Schlieker C, and Ploegh HL (2007) Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nat Chem Biol 3, 697-705.
    Pubmed CrossRef
  49. Brnjic S, Mazurkiewicz M, and Fryknäs M (2014) Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress. Antioxid Redox Signal 21, 2271-2285.
    Pubmed KoreaMed CrossRef
  50. Harrigan JA, Jacq X, and Martin NM (2017) Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov 17, 57-78.
    Pubmed CrossRef
  51. Okada K, Ye YQ, and Taniguchi K (2013) Vialinin A is a ubiquitin-specific peptidase inhibitor. Bioorg Med Chem Lett 23, 4328-4331.
    Pubmed CrossRef
  52. Yang J, Xu P, and Han L (2015) Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt. J Immunol 194, 4094-4097.
    Pubmed CrossRef
  53. Gavory G, O’dowd C, and McClelland K (2015) Abstract LB-257: Discovery and characterization of novel, highly potent and selective USP7 inhibitors. Cancer Res 75, 15.
    CrossRef
  54. Reverdy C, Conrath S, and Lopez R (2012) Discovery of Specific Inhibitors of Human USP7/HAUSP Deubiquitinating Enzyme. Chem Biol 19, 467-477.
    Pubmed CrossRef
  55. Colland F, Formstecher E, and Jacq X (2009) Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther 8, 2286-2295.
    Pubmed CrossRef
  56. Weinstock J, Wu J, and Cao P (2012) Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47. ACS Med Chem Lett 3, 789-792.
    Pubmed KoreaMed CrossRef
  57. Kapuria V, Peterson LF, Fang D, Bornmann WG, Talpaz M, and Donato NJ (2010) Deubiquitinase Inhibition by Small-Molecule WP1130 Triggers Aggresome Formation and Tumor Cell Apoptosis. Cancer Res 70, 9265-9276.
    Pubmed CrossRef
  58. Burkhart RA, Peng Y, and Norris ZA (2013) Mitoxantrone Targets Human Ubiquitin-Specific Peptidase 11 (USP11) and Is a Potent Inhibitor of Pancreatic Cancer Cell Survival. Mol Cancer Res 11, 901-911.
    Pubmed CrossRef
  59. Lee B-H, Lee MJ, and Park S (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179-184.
    Pubmed KoreaMed CrossRef
  60. Deng H, O’Keefe H, and Davie CP (2012) Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT). J Med Chem 55, 7061-7079.
    Pubmed CrossRef
  61. Yue W, Chen Z, and Liu H (2014) A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res 24, 482-496.
    Pubmed KoreaMed CrossRef
  62. Tian Z, D’Arcy P, and Wang X (2014) A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 123, 706-716.
    Pubmed KoreaMed CrossRef
  63. Gu Y, Ding X, and Huang J (2018) The deubiquitinating enzyme UCHL1 negatively regulates the immunosuppressive capacity and survival of multipotent mesenchymal stromal cells. Cell Death Dis 9, 459.
    Pubmed KoreaMed CrossRef
  64. D’Arcy P, Wang X, and Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147, 32-54.
    Pubmed CrossRef
  65. Lei H, Shan H, and Wu Y (2017) Targeting deubiquitinating enzymes in cancer stem cells. Cancer Cell Int 17, 101.
    Pubmed KoreaMed CrossRef
  66. Zou Y, Qiu G, and Jiang L (2017) Overexpression of ubiquitin specific proteases 44 promotes the malignancy of glioma by stabilizing tumor-promoter securin. Oncotarget 8, 58231-58246.
    Pubmed KoreaMed CrossRef
  67. Boustani MR, Khoshnood RJ, and Nikpasand F (2016) Overexpression of ubiquitin-specific protease 2a (USP2a) and nuclear factor erythroid 2-related factor 2 (Nrf2) in human gliomas. J Neurol Sci 363, 249-252.
    Pubmed CrossRef
  68. Zhang QX, Wang XC, Chen SP, and Qin XT (2016) Predictive value of deubiquitination enzymes USP37 in the prognosis of breast cancer. Zhonghua Yi Xue Za Zhi 96, 944-948.
    Pubmed CrossRef
  69. Qu Q, Mao Y, and Xiao G (2015) USP2 promotes cell migration and invasion in triple negative breast cancer cell lines. Tumor Biol 36, 5415-5423.
    Pubmed CrossRef
  70. Ni Q, Chen J, and Li X (2017) Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion. Acta Biochim Biophys Sin (Shanghai) 49, 680-688.
    Pubmed CrossRef
  71. Liu R, Zhao D, and Zhang X (2017) A20 enhances the radiosensitivity of hepatocellular carcinoma cells to 60Co-γ ionizing radiation. Oncotarget 8, 93103-93116.
    Pubmed KoreaMed CrossRef
  72. Yao R, Pu J, and Fan R (2017) Ubiquitin-specific protease 4 improves the prognosis of the patients in esophageal cancer. Cancer Biomarkers 20, 317-323.
    Pubmed CrossRef
  73. Baykara M, Yaman M, and Buyukberber S (2009) Clinical and prognostic importance of XIAP and USP8 in advanced stages of non-small cell lung cancer. J BUON 18, 921-927.
    Pubmed
  74. Kim Y, Shiba-Ishii A, and Nakagawa T (2017) Ubiquitin-specific protease 8 is a novel prognostic marker in early-stage lung adenocarcinoma. Pathol Int 67, 292-301.
    Pubmed CrossRef
  75. Zeng Z, Wu HX, and Zhan N (2014) Prognostic significance of USP10 as a tumor-associated marker in gastric carcinoma. Tumor Biol 35, 3845-3853.
    Pubmed CrossRef
  76. Zhang B, Wang H, and Yang L (2016) OTUD7B and NIK expression in non-small cell lung cancer: Association with clinicopathological features and prognostic implications. Pathol Res Pract 212, 893-898.
    Pubmed CrossRef
  77. McFarlane C, McFarlane S, and Paul I (2013) The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis. Oncotarget 4, 1836-1843.
    Pubmed KoreaMed CrossRef
  78. Peng L, Hu Y, Chen D, Jiao S, and Sun S (2016) Ubiquitin specific peptidase 21 regulates interleukin-8 expression, stem-cell like property of human renal cell carcinoma. Oncotarget 7, 42007-42016.
    Pubmed KoreaMed CrossRef
  79. Kim Y-H, Kim WT, and Jeong P (2014) Novel Combination Markers for Predicting Survival in Patients with Muscle Invasive Bladder Cancer: USP18 and DGCR2. J Korean Med Sci 29, 351.
    Pubmed KoreaMed CrossRef
  80. Yang M, Liu YD, Wang YY, Liu TB, Ge TT, and Lou G (2014) Ubiquitin-specific protease 22: a novel molecular biomarker in cervical cancer prognosis and therapeutics. Tumor Biol 35, 929-934.
    Pubmed CrossRef
  81. Piao S, Liu Y, and Hu J (2012) USP22 Is Useful as a Novel Molecular Marker for Predicting Disease Progression and Patient Prognosis of Oral Squamous Cell Carcinoma. PLoS One 7, e42540.
    Pubmed KoreaMed CrossRef
  82. Jia M, Guo Y, and Lu X (2018) USP33 is a Biomarker of Disease Recurrence in Papillary Thyroid Carcinoma. Cell Physiol Biochem 45, 2044-2053.
    Pubmed CrossRef
  83. Wang H, Li YP, and Chen JH (2013) Prognostic significance of USP22 as an oncogene in papillary thyroid carcinoma. Tumor Biol 34, 1635-1639.
    Pubmed CrossRef
  84. Guo G, Xu Y, Gong M, Cao Y, and An R (2014) USP28 is a potential prognostic marker for bladder cancer. Tumor Biol 35, 4017-4022.
    Pubmed CrossRef
  85. Li Y, Li J, Liu H, Liu Y, and Cui B (2017) Expression of MYSM1 is associated with tumor progression in colorectal cancer. PLoS One 12, e0177235.
    Pubmed KoreaMed CrossRef
  86. Liu H, Zhang Q, and Li K (2016) Prognostic significance of USP33 in advanced colorectal cancer patients: new insights into arrestin-dependent ERK signaling. Oncotarget 7, 81223-81240.
    Pubmed KoreaMed CrossRef
  87. Huang Y, Pan XW, and Li L (2016) Overexpression of USP39 predicts poor prognosis and promotes tumorigenesis of prostate cancer via promoting EGFR mRNA maturation and transcription elongation. Oncotarget 7, 22016-22030.
    Pubmed KoreaMed CrossRef
  88. Testa JR, Cheung M, and Pei J (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43, 1022-1025.
    Pubmed KoreaMed CrossRef
  89. Chiu HW, Lin HY, Tseng IJ, Hsiao M, and Lin YF (2018) OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast cancer. Oncotarget 9, 553-565.
    Pubmed KoreaMed CrossRef
  90. Arpalahti L, Saukkonen K, and Hagström J (2017) Nuclear ubiquitin C-terminal hydrolase L5 expression associates with increased patient survival in pancreatic ductal adenocarcinoma. Tumor Biol 39.
    Pubmed CrossRef
  91. Yang H, Zhang C, Fang S, Ou R, Li W, and Xu Y (2015) UCH-LI acts as a novel prognostic biomarker in gastric cardiac adenocarcinoma. Int J Clin Exp Pathol 8, 13957-13967.
    Pubmed KoreaMed
  92. Hussain S, Bedekovics T, Chesi M, Bergsagel PL, and Galardy PJ (2015) UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression. Oncotarget 6, 40704-40718.
    Pubmed KoreaMed CrossRef
  93. Kwon J, Mochida K, and Wang YL (2005) Ubiquitin C-Terminal Hydrolase L-1 Is Essential for the Early Apoptotic Wave of Germinal Cells and for Sperm Quality Control During Spermatogenesis. Biol Reprod 73, 29-35.
    Pubmed CrossRef
  94. Liu C, Liu C, and Liu H (2017) Increased Expression of Ubiquitin-Specific Protease 4 Participates in Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats. Cell Mol Neurobiol 37, 427-435.
    Pubmed CrossRef
  95. He B, Zhao YC, and Gao LC (2016) Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy. Hypertension 67, 1237-1248.
    Pubmed CrossRef
  96. Oliveira AM, and Chou MM (2014) USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst and nodular fasciitis. Hum Pathol 45, 1-11.
    Pubmed CrossRef
  97. Brackeva B, De Punt V, and Kramer G (2015) Potential of UCHL1 as biomarker for destruction of pancreatic beta cells. J Proteomics 117, 156-167.
    Pubmed CrossRef
  98. Lewis SB, Wolper R, and Chi YY (2010) Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 (UCHL1) as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res 88, 1475-1484.
    Pubmed CrossRef
  99. Papa L, Akinyi L, and Liu MC (2010) Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury. Crit Care Med 38, 138-144.
    Pubmed KoreaMed CrossRef
  100. Song YL, Yu R, and Qiao X-W (2017) Prognostic relevance of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors. Sci Rep 7, 2205.
    Pubmed KoreaMed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Funding Information

Services
Social Network Service

e-submission

Archives