BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Deubiquitinating enzymes as cancer biomarkers: new therapeutic opportunities?

  • Poondla, Naresh (Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Chandrasekaran, Arun Pandian (Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Kim, Kye-Seong (Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Ramakrishna, Suresh (Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University)
  • Received : 2019.01.10
  • Published : 2019.03.31
Download PDF
⟨ Previous Next ⟩

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

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
  2. Li J, Shen H and Himmel KL (1999) Leukaemia disease genes: large-scale cloning and pathway predictions. Nat Genet 23, 348-353 https://doi.org/10.1038/15531
  3. Hansen GM, Skapura D and Justice MJ (2000) Genetic profile of insertion mutations in mouse leukemias and lymphomas. Genome Res 10, 237-243 https://doi.org/10.1101/gr.10.2.237
  4. Fishel R, Lescoe MK, Rao MR et al (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027-1038 https://doi.org/10.1016/0092-8674(93)90546-3
  5. Sharma A, Alswillah T, Singh K et al (2018) USP14 regulates DNA damage repair by targeting RNF168-dependent ubiquitination. Autophagy 14, 1976-1990 https://doi.org/10.1080/15548627.2018.1496877
  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 https://doi.org/10.1002/stem.2446
  7. Lork M, Verhelst K and Beyaert R (2017) CYLD, A20 and OTULIN deubiquitinases in NF-${\kappa}B$ signaling and cell death: so similar, yet so different. Cell Death Differ 24, 1172-1183 https://doi.org/10.1038/cdd.2017.46
  8. Darling S, Fielding AB, Sabat-Pospiech D, Prior IA and Coulson JM (2017) Regulation of the cell cycle and centrosome biology by deubiquitylases. Biochem Soc Trans 45, 1125-1136 https://doi.org/10.1042/BST20170087
  9. Jacq X, Kemp M, Martin NMB and Jackson SP (2013) Deubiquitylating Enzymes and DNA Damage Response Pathways. Cell Biochem Biophys 67, 25-43 https://doi.org/10.1007/s12013-013-9635-3
  10. Nijman SMB, Luna-Vargas MPA and Velds A (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773-786 https://doi.org/10.1016/j.cell.2005.11.007
  11. Abdul Rehman SA, Kristariyanto YA, Choi SY et al (2016) MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes. Mol Cell 63, 146-155 https://doi.org/10.1016/j.molcel.2016.05.009
  12. Priolo C, Tang D, Brahamandan M et al (2006) The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Res 66, 8625-8632 https://doi.org/10.1158/0008-5472.CAN-06-1374
  13. Qu Q, Mao Y, Xiao G et al (2015) USP2 promotes cell migration and invasion in triple negative breast cancer cell lines. Tumor Biol 36, 5415-5423 https://doi.org/10.1007/s13277-015-3207-7
  14. Zhang L, Zhou F, Drabsch Y et al (2012) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-${\beta}$ type i receptor. Nat Cell Biol 14, 717-726 https://doi.org/10.1038/ncb2522
  15. Seibold MA and Schwartz DA (2011) The authors reply. N Engl J Med 364, 1503-1512 https://doi.org/10.1056/NEJMoa1013660
  16. Xing C, Lu XX, Guo P Da et al (2016) Ubiquitin-specific protease 4-mediated deubiquitination and stabilization of PRL-3 is required for potentiating colorectal oncogenesis. Cancer Res 76, 83-95 https://doi.org/10.1158/0008-5472.CAN-14-3595
  17. Guo W, Ma J, Pei T et al (2018) Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma. J Cell Mol Med 22, 2944-2954 https://doi.org/10.1111/jcmm.13603
  18. Li T, Yan B, Ma Y et al (2018) Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination. Cell Death Dis 9, 148-165 https://doi.org/10.1038/s41419-017-0182-5
  19. Cao WH, Liu XP, Meng SL et al (2016) USP4 promotes invasion of breast cancer cells via Relaxin/TGF-${\beta}$1/Smad2/MMP-9 signal. Eur Rev Med Pharmacol Sci 20, 1115-1122
  20. Hicke L (2001) Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2, 195-201 https://doi.org/10.1038/35056583
  21. Tang B, Tang F, Li B et al (2015) High USP22 expression indicates poor prognosis in hepatocellular carcinoma. Oncotarget 6, 12654-12667 https://doi.org/10.18632/oncotarget.3705
  22. Liu Y, Wang W, Lu Y et al (2017) Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma 8, 50655-50664 https://doi.org/10.18632/oncotarget.16901
  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 https://doi.org/10.1016/j.bbrc.2017.08.040
  24. Cheon KW and Baek KH (2006) HAUSP as a therapeutic target for hematopoietic tumors (Review). Int J Oncol 28, 1209-1215
  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 https://doi.org/10.1620/tjem.239.165
  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 https://doi.org/10.12659/MSM.909368
  27. Zhang C, Lu J, Zhang Q-W et al (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 https://doi.org/10.1016/j.biocel.2016.08.025
  28. Fraile JM, Quesada V, Rodriguez D, Freije JMP and Lopez-Otin C (2012) Deubiquitinases in cancer: New functions and therapeutic options. Oncogene 31, 2373-2388 https://doi.org/10.1038/onc.2011.443
  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 https://doi.org/10.1371/journal.pbio.1001238
  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 https://doi.org/10.1038/emboj.2010.100
  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 https://doi.org/10.12659/MSM.909235
  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 https://doi.org/10.1038/sj.onc.1204553
  33. Piao S, Ma J, Wang W et al (2013) Increased expression of USP22 is associated with disease progression and patient prognosis of salivary duct carcinoma. Oral Oncol 49, 796-801 https://doi.org/10.1016/j.oraloncology.2013.03.454
  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 https://doi.org/10.1007/s00432-012-1191-5
  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 https://doi.org/10.1007/s00335-010-9268-4
  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 https://doi.org/10.1111/cpr.12343
  37. Baietti MF, Simicek M, Abbasi Asbagh L et al (2016) OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination. EMBO Mol Med 8, 288-303 https://doi.org/10.15252/emmm.201505972
  38. Stanisic 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) ${\alpha}$ and Affects $ER{\alpha}$ Transcriptional Activity. J Biol Chem 284, 16135-16145 https://doi.org/10.1074/jbc.M109.007484
  39. Zhang Y, Hu R, Wu H et al (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 https://doi.org/10.1371/journal.pone.0029654
  40. Weng W, Zhang Q, Xu M et al (2016) OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma. Am J Transl Res 8, 2234-2244
  41. Xu L, Li J, Bao Z et al (2017) Silencing of OTUB1 inhibits migration of human glioma cells in vitro. Neuropathology 37, 217-226 https://doi.org/10.1111/neup.12366
  42. Catrysse L, Vereecke L, Beyaert R and van Loo G (2014) A20 in inflammation and autoimmunity. Trends Immunol 35, 22-31 https://doi.org/10.1016/j.it.2013.10.005
  43. Lee JH, Jung SM, Yang KM et al (2017) A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1. Nat Cell Biol 19, 1260-1273 https://doi.org/10.1038/ncb3609
  44. Ndubaku C and Tsui V (2015) Inhibiting the deubiquitinating enzymes (DUBs). J Med Chem 58, 1581-1595 https://doi.org/10.1021/jm501061a
  45. D'Arcy P, Wang X and Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147, 32-54 https://doi.org/10.1016/j.pharmthera.2014.11.002
  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 https://doi.org/10.1016/j.drudis.2018.05.035
  47. Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37, 937-953 https://doi.org/10.1042/BST0370937
  48. Love KR, Catic A, Schlieker C and Ploegh HL (2007) Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nat Chem Biol 3, 697-705 https://doi.org/10.1038/nchembio.2007.43
  49. Brnjic S, Mazurkiewicz M, Fryknas M et al (2014) Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress. Antioxid Redox Signal 21, 2271-2285 https://doi.org/10.1089/ars.2013.5322
  50. Harrigan JA, Jacq X, Martin NM et al (2017) Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov 17, 57-78 https://doi.org/10.1038/nrd.2017.152
  51. Okada K, Ye YQ, Taniguchi K et al (2013) Vialinin A is a ubiquitin-specific peptidase inhibitor. Bioorg Med Chem Lett 23, 4328-4331 https://doi.org/10.1016/j.bmcl.2013.05.093
  52. Yang J, Xu P, Han L et al (2015) Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing $ROR{\gamma}t$. J Immunol 194, 4094-4097 https://doi.org/10.4049/jimmunol.1401451
  53. Gavory G, O'dowd C, McClelland K et al (2015) Abstract LB-257: Discovery and characterization of novel, highly potent and selective USP7 inhibitors. Cancer Res 75, 15 https://doi.org/10.1158/1538-7445.AM2015-15
  54. Reverdy C, Conrath S, Lopez R et al (2012) Discovery of Specific Inhibitors of Human USP7/HAUSP Deubiquitinating Enzyme. Chem Biol 19, 467-477 https://doi.org/10.1016/j.chembiol.2012.02.007
  55. Colland F, Formstecher E, Jacq X et al (2009) Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther 8, 2286-2295 https://doi.org/10.1158/1535-7163.MCT-09-0097
  56. Weinstock J, Wu J, Cao P et al (2012) Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47. ACS Med Chem Lett 3, 789-792 https://doi.org/10.1021/ml200276j
  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 https://doi.org/10.1158/0008-5472.CAN-10-1530
  58. Burkhart RA, Peng Y, Norris ZA et al (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 https://doi.org/10.1158/1541-7786.MCR-12-0699
  59. Lee B-H, Lee MJ, Park S et al (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179-184 https://doi.org/10.1038/nature09299
  60. Deng H, O'Keefe H, Davie CP et al (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 https://doi.org/10.1021/jm300449x
  61. Yue W, Chen Z, Liu H et al (2014) A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res 24, 482-496 https://doi.org/10.1038/cr.2014.20
  62. Tian Z, D'Arcy P, Wang X et al (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 https://doi.org/10.1182/blood-2013-05-500033
  63. Gu Y, Ding X, Huang J et al (2018) The deubiquitinating enzyme UCHL1 negatively regulates the immunosuppressive capacity and survival of multipotent mesenchymal stromal cells. Cell Death Dis 9, 459 https://doi.org/10.1038/s41419-018-0532-y
  64. D'Arcy P, Wang X and Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147, 32-54 https://doi.org/10.1016/j.pharmthera.2014.11.002
  65. Lei H, Shan H and Wu Y (2017) Targeting deubiquitinating enzymes in cancer stem cells. Cancer Cell Int 17, 101 https://doi.org/10.1186/s12935-017-0472-0
  66. Zou Y, Qiu G, Jiang L et al (2017) Overexpression of ubiquitin specific proteases 44 promotes the malignancy of glioma by stabilizing tumor-promoter securin. Oncotarget 8, 58231-58246 https://doi.org/10.18632/oncotarget.16447
  67. Boustani MR, Khoshnood RJ, Nikpasand F et al (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 https://doi.org/10.1016/j.jns.2016.03.003
  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
  69. Qu Q, Mao Y, Xiao G et al (2015) USP2 promotes cell migration and invasion in triple negative breast cancer cell lines. Tumor Biol 36, 5415-5423 https://doi.org/10.1007/s13277-015-3207-7
  70. Ni Q, Chen J, Li X et al (2017) Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion. Acta Biochim Biophys Sin (Shanghai) 49, 680-688 https://doi.org/10.1093/abbs/gmx056
  71. Liu R, Zhao D, Zhang X et al (2017) A20 enhances the radiosensitivity of hepatocellular carcinoma cells to 60Co-$\gamma$ ionizing radiation. Oncotarget 8, 93103-93116 https://doi.org/10.18632/oncotarget.21860
  72. Yao R, Pu J, Fan R et al (2017) Ubiquitin-specific protease 4 improves the prognosis of the patients in esophageal cancer. Cancer Biomarkers 20, 317-323 https://doi.org/10.3233/CBM-170308
  73. Baykara M, Yaman M, Buyukberber S et al (2009) Clinical and prognostic importance of XIAP and USP8 in advanced stages of non-small cell lung cancer. J BUON 18, 921-927
  74. Kim Y, Shiba-Ishii A, Nakagawa T et al (2017) Ubiquitinspecific protease 8 is a novel prognostic marker in early-stage lung adenocarcinoma. Pathol Int 67, 292-301 https://doi.org/10.1111/pin.12546
  75. Zeng Z, Wu HX, Zhan N et al (2014) Prognostic significance of USP10 as a tumor-associated marker in gastric carcinoma. Tumor Biol 35, 3845-3853 https://doi.org/10.1007/s13277-013-1509-1
  76. Zhang B, Wang H, Yang L et al (2016) OTUD7B and NIK expression in non-small cell lung cancer: Association with clinicopathological features and prognostic implications. Pathol Res Pract 212, 893-898 https://doi.org/10.1016/j.prp.2016.07.011
  77. McFarlane C, McFarlane S, Paul I et al (2013) The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis. Oncotarget 4, 1836-1843 https://doi.org/10.18632/oncotarget.1282
  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 https://doi.org/10.18632/oncotarget.9751
  79. Kim Y-H, Kim WT, Jeong P et al (2014) Novel Combination Markers for Predicting Survival in Patients with Muscle Invasive Bladder Cancer: USP18 and DGCR2. J Korean Med Sci 29, 351 https://doi.org/10.3346/jkms.2014.29.3.351
  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 https://doi.org/10.1007/s13277-013-1121-4
  81. Piao S, Liu Y, Hu J et al (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 https://doi.org/10.1371/journal.pone.0042540
  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 https://doi.org/10.1159/000488041
  83. Wang H, Li YP, Chen JH et al (2013) Prognostic significance of USP22 as an oncogene in papillary thyroid carcinoma. Tumor Biol 34, 1635-1639 https://doi.org/10.1007/s13277-013-0696-0
  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 https://doi.org/10.1007/s13277-013-1525-1
  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 https://doi.org/10.1371/journal.pone.0177235
  86. Liu H, Zhang Q, Li K et al (2016) Prognostic significance of USP33 in advanced colorectal cancer patients: new insights into arrestin-dependent ERK signaling. Oncotarget 7, 81223-81240 https://doi.org/10.18632/oncotarget.13219
  87. Huang Y, Pan XW, Li L et al (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 https://doi.org/10.18632/oncotarget.7882
  88. Testa JR, Cheung M, Pei J et al (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43, 1022-1025 https://doi.org/10.1038/ng.912
  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 https://doi.org/10.18632/oncotarget.23074
  90. Arpalahti L, Saukkonen K, Hagstrom J et al (2017) Nuclear ubiquitin C-terminal hydrolase L5 expression associates with increased patient survival in pancreatic ductal adenocarcinoma. Tumor Biol 39, 101042831771041
  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
  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 https://doi.org/10.18632/oncotarget.5727
  93. Kwon J, Mochida K, Wang YL et al (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 https://doi.org/10.1095/biolreprod.104.037077
  94. Liu C, Liu C, Liu H et al (2017) Increased Expression of Ubiquitin-Specific Protease 4 Participates in Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats. Cell Mol Neurobiol 37, 427-435 https://doi.org/10.1007/s10571-016-0375-y
  95. He B, Zhao YC, Gao LC et al (2016) Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy. Hypertension 67, 1237-1248 https://doi.org/10.1161/HYPERTENSIONAHA.116.07392
  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 https://doi.org/10.1016/j.humpath.2013.03.005
  97. Brackeva B, De Punt V, Kramer G et al (2015) Potential of UCHL1 as biomarker for destruction of pancreatic beta cells. J Proteomics 117, 156-167 https://doi.org/10.1016/j.jprot.2015.01.009
  98. Lewis SB, Wolper R, Chi YY et al (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 https://doi.org/10.1002/jnr.22323
  99. Papa L, Akinyi L, Liu MC et al (2010) Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury. Crit Care Med 38, 138-144 https://doi.org/10.1097/CCM.0b013e3181b788ab
  100. Song YL, Yu R, Qiao X-W et al (2017) Prognostic relevance of UCH-L1 and ${\alpha}$-internexin in pancreatic neuroendocrine tumors. Sci Rep 7, 2205 https://doi.org/10.1038/s41598-017-02051-1