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Ubiquitin-specific peptidase 1: assessing its role in cancer therapy

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Abstract

Reversible protein ubiquitination represents an essential determinator of cellular homeostasis, and the ubiquitin-specific enzymes, particularly deubiquitinases (DUBs), are emerging as promising targets for drug development. DUBs are composed of seven different subfamilies, out of which ubiquitin-specific proteases (USPs) are the largest family with 56 members. One of the well-characterized USPs is USP1, which contributes to several cellular biological processes including DNA damage response, immune regulation, cell proliferation, apoptosis, and migration. USP1 levels and activity are regulated by multiple mechanisms, including transcription regulation, phosphorylation, autocleavage, and proteasomal degradation, ensuring that the cellular function of USP1 is performed in a suitably modulated spatio-temporal manner. Moreover, USP1 with deregulated expression and activity are found in several human cancers, indicating that targeting USP1 is a feasible therapeutic approach in anti-cancer treatment. In this review, we highlight the essential role of USP1 in cancer development and the regulatory landscape of USP1 activity, which might provide novel insights into cancer treatment.

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References

  1. Huibregtse JM. UPS shipping and handling. Cell. 2005;120(1):2–4. https://doi.org/10.1016/j.cell.2004.12.029.

    Article  CAS  PubMed  Google Scholar 

  2. Cruz Walma DA, Chen Z, Bullock AN, Yamada KM. Ubiquitin ligases: guardians of mammalian development. Nat Rev Mol Cell Biol. 2022;23(5):350–67. https://doi.org/10.1038/s41580-021-00448-5.

    Article  CAS  PubMed  Google Scholar 

  3. Rape M. Ubiquitylation at the crossroads of development and disease. Nat Rev Mol Cell Biol. 2018;19(1):59–70. https://doi.org/10.1038/nrm.2017.83.

    Article  CAS  PubMed  Google Scholar 

  4. Doerr A. Comprehensive mapping of ubiquitination. Nat Methods. 2018;15(9):651. https://doi.org/10.1038/s41592-018-0122-z.

    Article  CAS  PubMed  Google Scholar 

  5. Komander D, Rape M. The ubiquitin code. Annu Rev Biochem. 2012;81:203–29. https://doi.org/10.1146/annurev-biochem-060310-170328.

    Article  CAS  PubMed  Google Scholar 

  6. Komander D, Clague MJ, Urbé S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10(8):550–63. https://doi.org/10.1038/nrm2731.

    Article  CAS  PubMed  Google Scholar 

  7. Clague MJ, Urbé S, Komander D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol. 2019;20(6):338–52. https://doi.org/10.1038/s41580-019-0099-1.

    Article  CAS  PubMed  Google Scholar 

  8. Fujiwara T, Saito A, Suzuki M, et al. Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease. Genomics. 1998;54(1):155–8. https://doi.org/10.1006/geno.1998.5554.

    Article  CAS  PubMed  Google Scholar 

  9. Jang SW, Kim JM. Mutation of aspartic acid 199 in USP1 disrupts its deubiquitinating activity and impairs DNA repair. FEBS Lett. 2021;595(15):1997–2006. https://doi.org/10.1002/1873-3468.14152.

    Article  CAS  PubMed  Google Scholar 

  10. Cohn MA, Kee Y, Haas W, Gygi SP, D’Andrea AD. UAF1 is a subunit of multiple deubiquitinating enzyme complexes. J Biol Chem. 2009;284(8):5343–51. https://doi.org/10.1074/jbc.M808430200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Young MJ, Hsu KC, Lin TE, Chang WC, Hung JJ. The role of ubiquitin-specific peptidases in cancer progression. J Biomed Sci. 2019;26(1):42. https://doi.org/10.1186/s12929-019-0522-0.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pal A, Young MA, Donato NJ. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Can Res. 2014;74(18):4955–66. https://doi.org/10.1158/0008-5472.Can-14-1211.

    Article  CAS  Google Scholar 

  13. Kang JA, Jeon YJ. Emerging roles of USP18: from biology to pathophysiology. Int J Molr Sci. 2020. https://doi.org/10.3390/ijms21186825.

    Article  Google Scholar 

  14. Islam MT, Chen F, Chen H. The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics. Arch Biochem Biophys. 2021;701:108811. https://doi.org/10.1016/j.abb.2021.108811.

    Article  CAS  PubMed  Google Scholar 

  15. Wang F, Ning S, Yu B, Wang Y. USP14: structure, function, and target inhibition. Front Pharmacol. 2021;12:801328. https://doi.org/10.3389/fphar.2021.801328.

    Article  CAS  PubMed  Google Scholar 

  16. Li Q, Ye C, Tian T, et al. The emerging role of ubiquitin-specific protease 20 in tumorigenesis and cancer therapeutics. Cell Death Dis. 2022;13(5):434. https://doi.org/10.1038/s41419-022-04853-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chauhan R, Bhat AA, Masoodi T, et al. Ubiquitin-specific peptidase 37: an important cog in the oncogenic machinery of cancerous cells. J Exp Clini Cancer Res CR. 2021;40(1):356. https://doi.org/10.1186/s13046-021-02163-7.

    Article  CAS  Google Scholar 

  18. Morás AM, Henn JG, Steffens Reinhardt L, Lenz G, Moura DJ. Recent developments in drug delivery strategies for targeting DNA damage response in glioblastoma. Life Sci. 2021;287:120128. https://doi.org/10.1016/j.lfs.2021.120128.

    Article  CAS  PubMed  Google Scholar 

  19. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  20. O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547–60. https://doi.org/10.1016/j.molcel.2015.10.040.

    Article  CAS  PubMed  Google Scholar 

  21. Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332(2):237–48. https://doi.org/10.1016/j.canlet.2012.01.007.

    Article  CAS  PubMed  Google Scholar 

  22. Nalepa G, Clapp DW. Fanconi anaemia and cancer: an intricate relationship. Nat Rev Cancer. 2018;18(3):168–85. https://doi.org/10.1038/nrc.2017.116.

    Article  CAS  PubMed  Google Scholar 

  23. Sharp MF, Bythell-Douglas R, Deans AJ, Crismani W. The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target. Mol Cell. 2021;81(11):2278–89. https://doi.org/10.1016/j.molcel.2021.04.023.

    Article  CAS  PubMed  Google Scholar 

  24. Semlow DR, Walter JC. Mechanisms of vertebrate DNA interstrand cross-link repair. Annu Rev Biochem. 2021;90:107–35. https://doi.org/10.1146/annurev-biochem-080320-112510.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Y, Zhou X, Huang P. Fanconi anemia and ubiquitination. J Genet Genom Yi Chuan Xue Bao. 2007;34(7):573–80. https://doi.org/10.1016/s1673-8527(07)60065-4.

    Article  Google Scholar 

  26. Lemonidis K, Arkinson C, Rennie ML, Walden H. Mechanism, specificity, and function of FANCD2-FANCI ubiquitination and deubiquitination. FEBS J. 2021. https://doi.org/10.1111/febs.16077.

    Article  PubMed  Google Scholar 

  27. Kim JM, Parmar K, Huang M, et al. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell. 2009;16(2):314–20. https://doi.org/10.1016/j.devcel.2009.01.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oestergaard VH, Langevin F, Kuiken HJ, et al. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol Cell. 2007;28(5):798–809. https://doi.org/10.1016/j.molcel.2007.09.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liang F, Miller AS, Longerich S, et al. DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response. Nat Commun. 2019;10(1):2849. https://doi.org/10.1038/s41467-019-10408-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang TT, Nijman SM, Mirchandani KD, et al. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol. 2006;8(4):339–47. https://doi.org/10.1038/ncb1378.

    Article  CAS  PubMed  Google Scholar 

  31. Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature. 2002;419(6903):135–41. https://doi.org/10.1038/nature00991.

    Article  CAS  PubMed  Google Scholar 

  32. Friedberg EC, Lehmann AR, Fuchs RP. Trading places: how do DNA polymerases switch during translesion DNA synthesis? Mol Cell. 2005;18(5):499–505. https://doi.org/10.1016/j.molcel.2005.03.032.

    Article  CAS  PubMed  Google Scholar 

  33. Lee KY, Yang K, Cohn MA, et al. Human ELG1 regulates the level of ubiquitinated proliferating cell nuclear antigen (PCNA) through Its interactions with PCNA and USP1. J Biol Chem. 2010;285(14):10362–9. https://doi.org/10.1074/jbc.M109.092544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jones MJ, Colnaghi L, Huang TT. Dysregulation of DNA polymerase κ recruitment to replication forks results in genomic instability. EMBO J. 2012;31(4):908–18. https://doi.org/10.1038/emboj.2011.457.

    Article  CAS  PubMed  Google Scholar 

  35. Lim KS, Li H, Roberts EA, et al. USP1 is required for replication fork protection in BRCA1-deficient tumors. Mol Cell. 2018;72(6):925-941.e924. https://doi.org/10.1016/j.molcel.2018.10.045.

    Article  CAS  PubMed  Google Scholar 

  36. Guervilly JH, Renaud E, Takata M, Rosselli F. USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation. Hum Mol Genet. 2011;20(11):2171–81. https://doi.org/10.1093/hmg/ddr103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu Z, Song H, Jia M, et al. USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses. J Exp Med. 2017;214(12):3553–63. https://doi.org/10.1084/jem.20170180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Omilusik KD, Nadjsombati MS, Yoshida TM, et al. Ubiquitin specific protease 1 expression and function in T cell immunity. J Immunol (Baltimore Md: 1950). 2021;207(5):1377–87. https://doi.org/10.4049/jimmunol.2100303.

    Article  CAS  Google Scholar 

  39. Song H, Zhao C, Yu Z, et al. UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression. Nat Commun. 2020;11(1):6042. https://doi.org/10.1038/s41467-020-19939-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Knochelmann HM, Dwyer CJ, Bailey SR, et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 2018;15(5):458–69. https://doi.org/10.1038/s41423-018-0004-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Reiner SL. Development in motion: helper T cells at work. Cell. 2007;129(1):33–6. https://doi.org/10.1016/j.cell.2007.03.019.

    Article  CAS  PubMed  Google Scholar 

  42. Sfanos KS, Bruno TC, Maris CH, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clini Cancer Res Off J Am Assoc Cancer Res. 2008;14(11):3254–61. https://doi.org/10.1158/1078-0432.Ccr-07-5164.

    Article  CAS  Google Scholar 

  43. Duan MC, Han W, Jin PW, et al. Disturbed Th17/Treg balance in patients with non-small cell lung cancer. Inflammation. 2015;38(6):2156–65. https://doi.org/10.1007/s10753-015-0198-x.

    Article  CAS  PubMed  Google Scholar 

  44. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140(6):845–58. https://doi.org/10.1016/j.cell.2010.02.021.

    Article  CAS  PubMed  Google Scholar 

  45. Geng J, Yu S, Zhao H, et al. The transcriptional coactivator TAZ regulates reciprocal differentiation of T(H)17 cells and T(reg) cells. Nat Immunol. 2017;18(7):800–12. https://doi.org/10.1038/ni.3748.

    Article  CAS  PubMed  Google Scholar 

  46. Zhu X, Wang P, Zhan X, et al. USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ. Cell Mol Immunol. 2023;20(3):252–63. https://doi.org/10.1038/s41423-022-00969-9.

    Article  CAS  PubMed  Google Scholar 

  47. Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Can Res. 2011;71(4):1263–71. https://doi.org/10.1158/0008-5472.Can-10-2907.

    Article  CAS  Google Scholar 

  48. Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol. 2009;39(1):216–24. https://doi.org/10.1002/eji.200838475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lasorella A, Stegmüller J, Guardavaccaro D, et al. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature. 2006;442(7101):471–4. https://doi.org/10.1038/nature04895.

    Article  CAS  PubMed  Google Scholar 

  50. Williams SA, Maecker HL, French DM, et al. USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell. 2011;146(6):918–30. https://doi.org/10.1016/j.cell.2011.07.040.

    Article  CAS  PubMed  Google Scholar 

  51. Lee JK, Chang N, Yoon Y, et al. USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance. Neuro Oncol. 2016;18(1):37–47. https://doi.org/10.1093/neuonc/nov091.

    Article  CAS  PubMed  Google Scholar 

  52. Das DS, Das A, Ray A, et al. Blockade of deubiquitylating enzyme USP1 inhibits DNA repair and triggers apoptosis in multiple myeloma cells. Clini Cancer Res Off J Am Assoc Cancer Res. 2017;23(15):4280–9. https://doi.org/10.1158/1078-0432.Ccr-16-2692.

    Article  CAS  Google Scholar 

  53. Meng D, Li D. Ubiquitin-specific protease 1 overexpression indicates poor prognosis and promotes proliferation, migration, and invasion of gastric cancer cells. Tissue cell. 2022;74:101723. https://doi.org/10.1016/j.tice.2021.101723.

    Article  CAS  PubMed  Google Scholar 

  54. Ma A, Tang M, Zhang L, et al. USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis. Oncogene. 2019;38(13):2405–19. https://doi.org/10.1038/s41388-018-0590-8.

    Article  CAS  PubMed  Google Scholar 

  55. Wu Y, Wang Y, Lin Y, et al. Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation. Nat Commun. 2017;8:14228. https://doi.org/10.1038/ncomms14228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jing C, Li X, Zhou M, et al. The PSMD14 inhibitor Thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation. Theranostics. 2021;11(12):5847–62. https://doi.org/10.7150/thno.46109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Guo X, Zhu R, Luo A, et al. EIF3H promotes aggressiveness of esophageal squamous cell carcinoma by modulating snail stability. J Exp Clini Cancer Res CR. 2020;39(1):175. https://doi.org/10.1186/s13046-020-01678-9.

    Article  CAS  Google Scholar 

  58. Liu T, Yu J, Deng M, et al. CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nat Commun. 2017;8:13923. https://doi.org/10.1038/ncomms13923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sonego M, Pellarin I, Costa A, et al. USP1 links platinum resistance to cancer cell dissemination by regulating snail stability. Sci Adv. 2019;5(5):eaav3235. https://doi.org/10.1126/sciadv.aav3235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kamata YU, Sumida T, Kobayashi Y, et al. Introduction of ID2 enhances invasiveness in ID2-null oral squamous cell carcinoma cells via the SNAIL axis. Cancer Genom Proteom. 2016;13(6):493–7. https://doi.org/10.21873/cgp.20012.

    Article  CAS  Google Scholar 

  61. Li N, Wu L, Zuo X, et al. USP1 Promotes GC metastasis via stabilizing ID2. Dis Mark. 2021;2021:3771990. https://doi.org/10.1155/2021/3771990.

    Article  CAS  Google Scholar 

  62. Liao Y, Shao Z, Liu Y, et al. USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells. J Exp Clini Cancer Res CR. 2021;40(1):201. https://doi.org/10.1186/s13046-021-02008-3.

    Article  CAS  Google Scholar 

  63. Han D, Wang L, Chen B, et al. USP1-WDR48 deubiquitinase complex enhances TGF-β induced epithelial-mesenchymal transition of TNBC cells via stabilizing TAK1. Cell Cycle (Georgetown, Tex). 2021;20(3):320–31. https://doi.org/10.1080/15384101.2021.1874695.

    Article  CAS  PubMed  Google Scholar 

  64. Mussell A, Shen H, Chen Y, et al. USP1 regulates TAZ protein stability through ubiquitin modifications in breast cancer. Cancers. 2020. https://doi.org/10.3390/cancers12113090.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Yuan P, Feng Z, Huang H, et al. USP1 inhibition suppresses the progression of osteosarcoma via destabilizing TAZ. Int J Biol Sci. 2022;18(8):3122–36. https://doi.org/10.7150/ijbs.65428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ohsugi T, Yamaguchi K, Zhu C, et al. Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells. Oncogene. 2019;38(32):6051–64. https://doi.org/10.1038/s41388-019-0856-9.

    Article  CAS  PubMed  Google Scholar 

  67. Liao Y, Liu Y, Shao Z, et al. A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene. 2021;40(25):4291–306. https://doi.org/10.1038/s41388-021-01851-0.

    Article  CAS  PubMed  Google Scholar 

  68. Liao Y, Sun W, Shao Z, et al. A SIX1 degradation inducer blocks excessive proliferation of prostate cancer. Int J Biol Sci. 2022;18(6):2439–51. https://doi.org/10.7150/ijbs.67873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu Y, Davicioni E, Triche TJ, Merlino G. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Can Res. 2006;66(4):1982–9. https://doi.org/10.1158/0008-5472.Can-05-2360.

    Article  CAS  Google Scholar 

  70. Li Z, Tian T, Lv F, et al. Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PloS one. 2013;8(3):e59203. https://doi.org/10.1371/journal.pone.0059203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Antonenko SV, Gurianov DS, Telegeev GD. Colocalization of USP1 and PH domain of Bcr­Abl oncoprotein in terms of cronic myeloid leukemia cell rearrangements. Tsitol Genet. 2016;50(4):11–5.

    CAS  PubMed  Google Scholar 

  72. Mistry H, Hsieh G, Buhrlage SJ, et al. Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther. 2013;12(12):2651–62. https://doi.org/10.1158/1535-7163.Mct-13-0103-t.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jiang S, Wang X, He Y, et al. Suppression of USP7 induces BCR-ABL degradation and chronic myelogenous leukemia cell apoptosis. Cell Death Dis. 2021;12(5):456. https://doi.org/10.1038/s41419-021-03732-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kuang X, Xiong J, Lu T, et al. Inhibition of USP1 induces apoptosis via ID1/AKT pathway in B-cell acute lymphoblastic leukemia cells. Int J Med Sci. 2021;18(1):245–55. https://doi.org/10.7150/ijms.47597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nijman SM, Huang TT, Dirac AM, et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005;17(3):331–9. https://doi.org/10.1016/j.molcel.2005.01.008.

    Article  CAS  PubMed  Google Scholar 

  76. Rego MA, Harney JA, Mauro M, Shen M, Howlett NG. Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor. Oncogene. 2012;31(3):366–75. https://doi.org/10.1038/onc.2011.237.

    Article  CAS  PubMed  Google Scholar 

  77. Rahme GJ, Zhang Z, Young AL, et al. PDGF engages an E2f-USP1 signaling pathway to support id2-mediated survival of proneural glioma Cells. Can Res. 2016;76(10):2964–76. https://doi.org/10.1158/0008-5472.Can-15-2157.

    Article  CAS  Google Scholar 

  78. Ma L, Lin K, Chang G, et al. Aberrant activation of β-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2. Can Res. 2019;79(1):72–85. https://doi.org/10.1158/0008-5472.Can-18-1304.

    Article  CAS  Google Scholar 

  79. Mohanty A, Nam A, Pozhitkov A, et al. A non-genetic mechanism involving the integrin β4/paxillin axis contributes to chemoresistance in lung cancer. iScience. 2020;23(9):101496. https://doi.org/10.1016/j.isci.2020.101496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gong H, Liu L, Cui L, Ma H, Shen L. ALKBH5-mediated m6A-demethylation of USP1 regulated T-cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B. Mol Carcinog. 2021;60(9):644–57. https://doi.org/10.1002/mc.23330.

    Article  CAS  PubMed  Google Scholar 

  81. Yates LA, Norbury CJ, Gilbert RJ. The long and short of microRNA. Cell. 2013;153(3):516–9. https://doi.org/10.1016/j.cell.2013.04.003.

    Article  CAS  PubMed  Google Scholar 

  82. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597–610. https://doi.org/10.1038/nrg2843.

    Article  CAS  PubMed  Google Scholar 

  83. Dong H, Lei J, Ding L, et al. MicroRNA: function, detection, and bioanalysis. Chem Rev. 2013;113(8):6207–33. https://doi.org/10.1021/cr300362f.

    Article  CAS  PubMed  Google Scholar 

  84. Flammang I, Reese M, Yang Z, Eble JA, Dhayat SA. Tumor-suppressive miR-192–5p has prognostic value in pancreatic ductal adenocarcinoma. Cancers. 2020. https://doi.org/10.3390/cancers12061693.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Yin S, Jin W, Qiu Y, et al. Solamargine induces hepatocellular carcinoma cell apoptosis and autophagy via inhibiting LIF/miR-192-5p/CYR61/Akt signaling pathways and eliciting immunostimulatory tumor microenvironment. J Hematol Oncol. 2022;15(1):32. https://doi.org/10.1186/s13045-022-01248-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zou P, Zhu M, Lian C, et al. miR-192-5p suppresses the progression of lung cancer bone metastasis by targeting TRIM44. Sci Rep. 2019;9(1):19619. https://doi.org/10.1038/s41598-019-56018-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhou S, Xiong M, Dai G, et al. MicroRNA-192-5p suppresses the initiation and progression of osteosarcoma by targeting USP1. Oncol Lett. 2018;15(5):6947–56. https://doi.org/10.3892/ol.2018.8180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Xu J, Li B, Song W, et al. Tumor suppressor functions of miRNA-375 in nasopharyngeal carcinoma through inhibition of ubiquitin-specific protease 1 expression. Int J Biochem Cell Biol. 2021;141:106092. https://doi.org/10.1016/j.biocel.2021.106092.

    Article  CAS  PubMed  Google Scholar 

  89. Cotto-Rios XM, Jones MJ, Busino L, Pagano M, Huang TT. APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage. J Cell Biol. 2011;194(2):177–86. https://doi.org/10.1083/jcb.201101062.

    Article  CAS  PubMed  Google Scholar 

  90. Cataldo F, Peche LY, Klaric E, et al. CAPNS1 regulates USP1 stability and maintenance of genome integrity. Mol Cell Biol. 2013;33(12):2485–96. https://doi.org/10.1128/mcb.01406-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cotto-Rios XM, Jones MJ, Huang TT. Insights into phosphorylation-dependent mechanisms regulating USP1 protein stability during the cell cycle. Cell Cycle (Georgetown, Tex). 2011;10(23):4009–16. https://doi.org/10.4161/cc.10.23.18501.

    Article  CAS  PubMed  Google Scholar 

  92. Villamil MA, Liang Q, Chen J, et al. Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1. Biochemistry. 2012;51(45):9112–23. https://doi.org/10.1021/bi300845s.

    Article  CAS  PubMed  Google Scholar 

  93. Liu J, Zhu H, Zhong N, et al. Gene silencing of USP1 by lentivirus effectively inhibits proliferation and invasion of human osteosarcoma cells. Int J Oncol. 2016;49(6):2549–57. https://doi.org/10.3892/ijo.2016.3752.

    Article  CAS  PubMed  Google Scholar 

  94. Gonzalez-Fierro A, Dueñas-González A. Drug repurposing for cancer therapy, easier said than done. Semin Cancer Biol. 2021;68:123–31. https://doi.org/10.1016/j.semcancer.2019.12.012.

    Article  PubMed  Google Scholar 

  95. Pilié PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16(2):81–104. https://doi.org/10.1038/s41571-018-0114-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen J, Dexheimer TS, Ai Y, 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(11):1390–400. https://doi.org/10.1016/j.chembiol.2011.08.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sourisseau T, Helissey C, Lefebvre C, et al. Translational regulation of the mRNA encoding the ubiquitin peptidase USP1 involved in the DNA damage response as a determinant of Cisplatin resistance. Cell Cycle (Georgetown, Tex). 2016;15(2):295–302. https://doi.org/10.1080/15384101.2015.1120918.

    Article  CAS  PubMed  Google Scholar 

  98. Cui SZ, Lei ZY, Guan TP, et al. Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Sci. 2020;111(5):1567–81. https://doi.org/10.1111/cas.14375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang L, Hu T, Shen Z, et al. Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC. Cell Death Dis. 2022;13(11):951. https://doi.org/10.1038/s41419-022-05341-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Liu Y, Kong WY, Yu CF, et al. SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta Pharmacol Sin. 2022. https://doi.org/10.1038/s41401-022-01003-4.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Chen Z, Ma Y, Guo Z, et al. Ubiquitin-specific protease 1 acts as an oncogene and promotes lenvatinib efficacy in hepatocellular carcinoma by stabilizing c-kit. Ann Hepatol. 2022;27(2):100669. https://doi.org/10.1016/j.aohep.2022.100669.

    Article  CAS  PubMed  Google Scholar 

  102. Liang Q, Dexheimer TS, Zhang P, et al. A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses. Nat Chem Biol. 2014;10(4):298–304. https://doi.org/10.1038/nchembio.1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dexheimer TS, Rosenthal AS, Luci DK, et al. Synthesis and structure-activity relationship studies of N-benzyl-2-phenylpyrimidin-4-amine derivatives as potent USP1/UAF1 deubiquitinase inhibitors with anticancer activity against nonsmall cell lung cancer. J Med Chem. 2014;57(19):8099–110. https://doi.org/10.1021/jm5010495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dexheimer TS, Rosenthal AS, Liang Q, et al. Discovery of ML323 as a novel inhibitor of the USP1/UAF1 deubiquitinase complex. In: Bethesda A, editor., et al., Probe reports from the NIH molecular libraries program. Bethesda: National Center for Biotechnology Information; 2010.

    Google Scholar 

  105. Lackner LL, Nunnari J. Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine. Chem Biol. 2010;17(6):578–83. https://doi.org/10.1016/j.chembiol.2010.05.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dong L, He J, Luo L, Wang K. Targeting the interplay of autophagy and ROS for cancer therapy: an updated overview on phytochemicals. Pharmaceuticals (Basel, Switzerland). 2023. https://doi.org/10.3390/ph16010092.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Sun Y, Sha B, Huang W, et al. ML323, a USP1 inhibitor triggers cell cycle arrest, apoptosis and autophagy in esophageal squamous cell carcinoma cells. Apoptosis Int J Program cell Death. 2022;27(7–8):545–60. https://doi.org/10.1007/s10495-022-01736-x.

    Article  CAS  Google Scholar 

  108. Lu Z, Zhang Z, Yang M, Xiao M. Ubiquitin-specific protease 1 inhibition sensitizes hepatocellular carcinoma cells to doxorubicin by ubiquitinated proliferating cell nuclear antigen-mediated attenuation of stemness. Anticancer Drugs. 2022;33(7):622–31. https://doi.org/10.1097/cad.0000000000001311.

    Article  CAS  PubMed  Google Scholar 

  109. Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell. 2009;138(2):389–403. https://doi.org/10.1016/j.cell.2009.04.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Doherty LM, Mills CE, Boswell SA, et al. Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes. eLife. 2022. https://doi.org/10.7554/eLife.72879.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Professor Qiu Li for the writing assistance and proofreading the article.

Funding

This research was supported by Science & Technology Department of Sichuan Province Funding Project (2022YFSY0027-Q.L) and Science & Technology Department of Sichuan Province Funding Project (2022NSFSC1348-PF.Z).

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Author notes

  1. Peng Huang and YuHan Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Peng Huang, PengFei Zhang & Qiu Li

  2. West China Biomedical Big Data Center, Sichuan University, Chengdu, 610041, Sichuan, China

    Peng Huang, PengFei Zhang & Qiu Li

  3. Department of Anorectal, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    YuHan Wang

  4. School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China

    YuHan Wang

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  1. Peng Huang
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Contributions

PH and YHW conceptualized the study, contributed to the preparation of the initial draft of the manuscript, and designed the figures, and tables. PFZ conceptualized the study, critically revised the manuscript, and administered the project. QL supervised the project and contributed to manuscript revision. All authors have read and approved the submitted version.

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Correspondence to Qiu Li.

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Huang, P., Wang, Y., Zhang, P. et al. Ubiquitin-specific peptidase 1: assessing its role in cancer therapy. Clin Exp Med 23, 2953–2966 (2023). https://doi.org/10.1007/s10238-023-01075-4

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