Facts

  • USP3 regulates the DNA damage response, and USP3 deficiency results in impaired cytogenetic stability.

  • USP3 is involved in cell cycle regulation and affects cell division and proliferation.

  • USP3 plays different roles in different cancers and functions as an oncogene in most cancers.

Open Questions

  • There are no targeted therapeutic agents or inhibitors for USP3, an area where current research is lacking.

  • Research on USP3 in cancer is still limited to cellular and animal models, and further clinical trials are necessary.

  • The regulatory mechanisms regarding USP3 are not sufficiently detailed and complete, and further in-depth investigation may be required in the future.

Introduction

Ubiquitination, a widespread post-translational modification, plays a crucial role in regulating cellular functions, with the majority of cellular proteins undergoing ubiquitination [1]. The ubiquitin molecule consists of 76 amino acids that exhibit a high degree of conservation throughout evolutionary processes [2]. Ubiquitin attaches covalently to lysine residues on the substrate through a series of enzymatic reactions involving ubiquitin-activating (E1s), ubiquitin-conjugating (E2s), and ubiquitin ligase (E3s) enzymes [3,4,5], resulting in mono-ubiquitination (single ubiquitin) and poly-ubiquitination (ubiquitin chains) [6]. The ubiquitin-proteasome system (UPS) governs the degradation of over 80% of intracellular proteins, oversees protein quality control, and upholds protein homeostasis [7].

Ubiquitination is a reversible process that is accomplished by deubiquitinases (DUBs). The approximately 100 DUBs in the human body are categorized into nine families [8]: ubiquitin‐specific proteases (USPs), ovarian tumor proteases (OTUs), ubiquitin C‐terminal hydrolases (UCHs), Machado‐Joseph domain‐containing proteases (MJDs, also known as Josephins), JAMM/MPN domain‐associated Zn‐depend metalloproteases (JAMMs, also known as MPN+), the motif interacting with ubiquitin (MIU)‐containing novel DUB family (MINDYs), monocyte chemotactic protein‐induced proteins (MCPIPs), permuted papain fold peptidases of dsRNA viruses and eukaryotes (PPPDEs), and zinc finger (ZnF) containing ubiquitin peptidase 1 (ZUP1) [9]. A burgeoning volume of researches has demonstrated that dysregulation of the balance between ubiquitination and deubiquitination can lead to a wide variety of adverse consequences [10]. USP3 is a member of the USPs, the largest family in DUBs. As the study of USP3 continues, researchers have found that USP3 is involved in a variety of physiological and pathological processes in cell. In the realm of innate immunity, USP3 plays a role in dampening antiviral responses by impeding the activation of the type I interferon (IFN) pathway through the elimination of Lysine 63 (K63)-linked polyubiquitin chains on RIG-I [11]. Within the context of renal cell carcinoma (RCC), the tumor suppressor E74-like transcription factor 5 has the ability to hinder the progression of RCC by promoting USP3-mediated deubiquitination and stabilization of WD40 and tetratricopeptide repeats 1 [12]. The multifaceted role of USP3 in various physiological processes underscores the importance of comprehensively investigating its structure, functions, and regulatory mechanisms, as such insights may offer novel therapeutic opportunities in the future. This review provides a comprehensive overview of the structure, functions, regulation and current research on USP3 in tumors and other diseases, and discusses the gaps and prospects for USP3 research. Particularly, the timeline of USP3 is listed in Fig. 1.

Fig. 1: Timeline of USP3 research.
figure 1

A number of studies of significance and relevance to disease and signalling pathways are listed to show the broad framework of USP3 research.

Full size image

The structure of USP3

USP3, located on human chromosome 15q22.31, contains 520 amino acid residues. USP3 contains two conserved protein domains: the ZnF domain and the catalytic domain (UCH) [13]. Amino acids 1–121 constitute the UBP ZnF, whereas amino acids 159–511 constitute the UCH. The structure of the UBP ZnF domain is unique and does not resemble any other known structure. It has a compact globular fold with a deep cleft and a pocket accommodating the C terminus of ubiquitin (Fig. 2) [14]. The core catalytic structure of USPs is generally composed of three subdomains, which have been likened to the palm, thumb, and finger. The “fingers” are responsible for grabbing ubiquitin and the catalytic center is between the “palm” and the “thumb” [15]. The catalytic core domain of USPs contains a conserved cysteine catalytic triad, and the extended finger domain, together with the palm and thumb domains, forms the binding pocket of ubiquitin that recognizes the extended tail of ubiquitin and presents its c terminus to the active site cysteine [16]. ZnF and UCH jointly function, both are indispensable. Experiments confirmed that mutation of UBP ZnF significantly reduced the interaction of USP3 with ubiquitinated histone uH2A both in vivo and in vitro, suggesting that this is the major domain mediating the interaction between USP3 and ubiquitin [17]. In addition, USP3 was found to inhibit type I IFN signaling by deubiquitinating RIG-I-like receptors. However, the ZnF domain of USP3 alone cannot inhibit RIG-I-induced type I IFN activation, and the UCH domain may require ZnF for maximal catalytic activity, suggesting that both intact ZnF and the catalytic domain are required for USP3 to exert its deubiquitination function [11]. USP3 has the capability to interact with Claspin via the UCH domain for the purpose of deubiquitinating it, resulting in the activation of Claspin-dependent ATR-Chk1 signaling that ultimately contributes to the augmentation of glioblastoma radiation resistance [18]. In summary, the biological activity of USP3 is contingent upon the structural integrity of its UBP ZnF and UCH domains, which work in tandem to fulfill the physiological role of USP3.

Fig. 2: The structure and domains of USP3.
figure 2

Amino acids 1-121 form the Ub-binding domain Zinc finger and amino acids 159-511 comprise the catalytic domain of Ub-specific protease.

Full size image

The functions of USP3

USP3 is a cysteine protease involved in a variety of physiological activities and perturbations in its function can result in adverse consequences. USP3 is implicated in DNA repair, cell cycle regulation, and apoptosis, with a particular focus on describing its role in maintaining genome stability and modulating inflammation.

In genome stability

Genomic instability is deemed to be a hallmark of cancer [19]. DNA is vulnerable to alterations caused by external and internal factors, leading organisms to safeguard the genome via the DNA damage response (DDR) and cell-cycle checkpoints [20]. The DDR comprises two main signaling pathways: ATR-CHK1 and ATM-CHK2, with checkpoint kinase 1 (CHK1) being activated by phosphorylation from the upstream kinase ATR [21]. The interaction between USP3 and CHK1 results in the direct removal of the inhibitory ubiquitin chain at K63, leading to the release of CHK1 from chromatin and subsequent down-regulation of USP3, which enhances gene stability [22]. Histone ubiquitination is essential for the activation of DDR, and USP3 acts as a chromatin modifier by deubiquitinating monoubiquitinated H2A (uH2A) and H2B (uH2B) in vivo. The ZnF domain and uH2A are identified as the major structural domains and substrates, respectively, for USP3-mediated deubiquitination [17]. Further studies revealed that in addition to uH2A, USP3 also deubiquitinates conjugate Ub-γH2AX (variant H2A) at K13-15. In addition, USP3 regulates the aggregation of DDR factors (BRCA1 and 53BP1) at DNA damage sites, and overexpression of USP3 impairs the recruitment of these factors [23]. USP3 regulates mitotic progression, and USP3 deficiency induces DNA damage leading to replication defects and S-phase delays as well as activation of the corresponding checkpoints [17]. USP3 deubiquitinates and stabilizes the cell division cycle 25A (Cdc25A), a bispecific phosphatase that regulates the cell cycle, and degradation of Cdc25A in the presence of DNA damage causes cells to arrest in G1 phase [24]. Stem cell homeostasis is also critical for maintaining genomic stability. USP3-deficient mouse models exhibit severe haematopoietic impairment and hematopoietic stem cell (HSC) defects, with a decline in lymphocytes as they age, particularly in B-cell lines and T-cell lines. USP3 shields HSC from ionizing radiation (IR) and defends against spontaneous DNA damage in vivo via ubiquitin-dependent DDR. Deficiency of USP3 makes HSC more sensitive to genotoxicity and contributes to severe genomic rearrangements due to spontaneously generated DSB-triggered repair pathways [25].

In inflammatory vesicles

Inflammatory vesicles are integral to the innate immune system, aiding in immune homeostasis, with NLRP3 inflammasomes being the subject of extensive research [26]. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) functions as a central bridging protein for multiple inflammatory vesicles, with USP3 playing a role in enhancing ASC stability through the removal of K48-linked ubiquitin chains. The formation of ASC speckles is indicative of NLRP3 inflammatory vesicle activation, with USP3 knockdown resulting in a significant reduction in the number of ASC speckles. Furthermore, in addition to NLRP3, USP3 overexpression in vivo also facilitates the activation of AIM2 and NLRC4 [27]. USP3, serving as a regulator of inflammatory vesicle activation, plays a crucial role in the precise control of inflammation and the maintenance of immune homeostasis.

Signaling pathways in USP3

USP3 is engaged in regulating multiple signaling pathways, such as type I IFN, NF-κB, and PI3K/AKT signaling pathways. This review specifically focuses on elucidating the mechanisms involved in the type I IFN and NF-κB pathways, which are crucial components of the innate immune system and are activated upon detection of pathogenic molecules by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), Nod-like receptors (NLRs), and RIG-I-like receptors (RLRs) [28].

Type I IFN signaling

Type I IFN, a cytokine produced in response to viral infection, is generated through PRR-mediated mechanisms. RLRs serve as intracellular PRRs for pathogen detection, with humans possessing three RLRs: RIG-I, melanoma differentiation-associated gene 5 (MDA5), and LGP2 [29, 30]. The N-terminal caspase activation recruitment domain (CARD) of RIG-I and MDA5 interacts with the mitochondrial protein MASV (mitochondrial antiviral signaling) in a ligand-dependent manner. USP3 modulates the type I IFN response by specifically binding to the CARD domains of RIG-I and MDA5, thereby inhibiting their activation. USP3 selectively cleaves the K63-linked ubiquitin chains on RIG-I, which are crucial for initiating the type I IFN response, without affecting ubiquitin chains on other signaling proteins [11]. Influenza A virus (IAV), which has caused several world pandemics, is highly pathogenic to humans, and the IFN pathway is one of the effective ways to combat it. USP3 is a negative regulator of the type I IFN pathway, and miR-26a can attack USP3 to activate the IFN pathway and thus inhibit IAV infection [31].

NF-κB signaling

In addition to its role in the type I IFN pathway, USP3 also negatively regulates the NF-κB signaling pathway induced by TLRs. USP3 plays a critical role in inhibiting NF-κB activation induced by TLR and IL-1R signaling through cytoplasmic translocation and cleavage of K63-linked ubiquitin chains on the adapter protein MyD88. USP3 is a key component of the MyD88-USP3 axis, essential for the development of innate immune tolerance [

References

  1. Mevissen TET, Komander D. Mechanisms of Deubiquitinase Specificity and Regulation. In: Kornberg RD, editor. Annu Rev Biochem. 2017;86:159–92.

  2. Schwartz AL, Ciechanover A. Targeting Proteins for Destruction by the Ubiquitin System: Implications for Human Pathobiology. Annu Rev Pharm Toxicol. 2009;49:73–96.

    Article  CAS  Google Scholar 

  3. Schulman BA, Harper JW. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009;10:319–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ye YH, Rape M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol. 2009;10:755–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buetow L, Huang DT. Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol. 2016;17:626–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Komander D, Rape M. The Ubiquitin Code. In: Kornberg RD, editor. Annu Rev Biochem. 2012;81:203–29.

  7. Yu ZD, Li H, Zhu J, Wang HB, ** XF. The roles of E3 ligases in Hepatocellular carcinoma. Am J Cancer Res. 2022;12:1179–214.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Grabbe C, Husnjak K, Dikic I. The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol. 2011;12:295–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ren J, Yu P, Liu SJ, Li R, Niu X, Chen Y, et al. Deubiquitylating Enzymes in Cancer and Immunity. Adv Sci. 2023;10:37.

    Article  Google Scholar 

  10. Ge FJ, Li YK, Yuan T, Wu YL, He QJ, Yang B, et al. Deubiquitinating enzymes: Promising targets for drug resistance. Drug Discov Today. 2022;27:2603–13.

    Article  CAS  PubMed  Google Scholar 

  11. Cui J, Song YX, Li YY, Zhu QY, Tan P, Qin YF, et al. USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res. 2014;24:400–16.

    Article  CAS  PubMed  Google Scholar 

  12. Li TS, Xu LJ, Wei Z, Zhang SM, Liu XY, Yang YZ, et al. ELF5 drives angiogenesis suppression though stabilizing WDTC1 in renal cell carcinoma. Mol Cancer. 2023;22:16.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sloper-Mould KE, Eyre HJ, Wang XW, Sutherland GR, Baker RT. Characterization and chromosomal localization of USP3, a novel human ubiquitin-specific protease. J Biol Chem. 1999;274:26878–84.

    Article  CAS  PubMed  Google Scholar 

  14. Reyes-Turcu FE, Horton JR, Mullally JE, Heroux A, Cheng XD, Wilkinson KD. The ubiquitin binding domain ZnFUBP recognizes the C-terminal diglycine motif of unanchored ubiquitin. Cell. 2006;124:1197–208.

    Article  CAS  PubMed  Google Scholar 

  15. Villamil MA, Liang Q, Zhuang ZH. The WD40-Repeat Protein-Containing Deubiquitinase Complex: Catalysis, Regulation, and Potential for Therapeutic Intervention. Cell Biochem Biophys. 2013;67:111–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yin JP, Schoeffler AJ, Wickliffe K, Newton K, Starovasnik MA, Dueber EC, et al. Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46. Structure. 2015;23:2043–54.

    Article  CAS  PubMed  Google Scholar 

  17. Nicassio F, Corrado N, Vissers JHA, Areces LB, Bergink S, Marteijn JA, et al. Human USP3 is a chromatin modifier required for S phase progression and genome stability. Curr Biol. 2007;17:1972–7.

    Article  CAS  PubMed  Google Scholar 

  18. Tu YM, Chen ZY, Zhao PZ, Sun GC, Bao ZY, Chao HL, et al. Smoothened Promotes Glioblastoma Radiation Resistance Via Activating USP3-Mediated Claspin Deubiquitination. Clin Cancer Res. 2020;26:1749–62.

    Article  CAS  PubMed  Google Scholar 

  19. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  20. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ciccia A, Elledge SJ. The DNA Damage Response: Making It Safe to Play with Knives. Mol Cell. 2010;40:179–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cheng YC, Shieh SY. Deubiquitinating enzyme USP3 controls CHK1 chromatin association and activation. Proc Natl Acad Sci USA. 2018;115:5546–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sharma N, Zhu QZ, Wani G, He JS, Wang QE, Wani AA. USP3 counteracts RNF168 via deubiquitinating H2A and gamma H2AX at lysine 13 and 15. Cell Cycle. 2014;13:106–14.

    Article  CAS  PubMed  Google Scholar 

  24. Das S, Chandrasekaran AP, Suresh B, Haq S, Kang JH, Lee SJ, et al. Genome-scale screening of deubiquitinase subfamily identifies USP3 as a stabilizer of Cdc25A regulating cell cycle in cancer. Cell Death Differ. 2020;27:3004–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lancini C, van den Berk PCM, Vissers JHA, Gargiulo G, Song JY, Hulsman D, et al. Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells. J Exp Med. 2014;211:1759–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhuang WX, Zhang L, Zheng Y, Liu BY, Ma CH, Zhao W, et al. USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation. Cell Mol Immunol. 2022;19:1141–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216.

    Article  CAS  PubMed  Google Scholar 

  29. Ablasser A, Hur S. Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nat Immunol. 2020;21:17–29.

    Article  CAS  PubMed  Google Scholar 

  30. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005;175:2851–8.

    Article  CAS  PubMed  Google Scholar 

  31. Gao SJ, Li JD, Song LP, Wu JX, Huang WL. Influenza A virus-induced downregulation of miR-26a contributes to reduced IFNα/β production. Virol Sin. 2017;32:261–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Duan TH, Feng YC, Du Y, **ng CS, Chu JJ, Ou JY, et al. USP3 plays a critical role in the induction of innate immune tolerance. EMBO Rep. 2023;24:21.

    Article  Google Scholar 

  33. Jia H, Duan L, Yu P, Zhou Y, Liu RR, Wang H. Digoxin ameliorates joint inflammatory microenvironment by downregulating synovial macrophage M1-like-polarization and its-derived exosomal miR-146b-5p/Usp3&Sox5 axis. Int Immunopharmacol. 2022;111:13.

    Article  Google Scholar 

  34. Zhao SM, Zheng BS, Wang LL, Cui WZ, Jiang CL, Li Z, et al. Deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners. Chin Med J. 2022;135:2706–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Smyth EC, Nilsson M, Grabsch HI, van Grieken NCT, Lordick F. Gastric cancer. Lancet. 2020;396:635–48.

    Article  CAS  PubMed  Google Scholar 

  36. Wu XS, Liu MW, Zhu HQ, Wang J, Dai WY, Li JY, et al. Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer. J Exp Clin Cancer Res. 2019;38:15.

    Article  Google Scholar 

  37. Fang CL, Lin CC, Chen HK, Hseu YC, Hung ST, Sun DP, et al. Ubiquitin-specific protease 3 overexpression promotes gastric carcinogenesis and is predictive of poor patient prognosis. Cancer Sci. 2018;109:3438–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wu XS, Wang H, Zhu DP, Chai YX, Wang J, Dai WY, et al. USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation. Cell Death Dis. 2022;13:11.

    Google Scholar 

  39. Li BJ, ** MM, Cao FF, Li J, Wu J, Xu LM, et al. Hsa_circ_0017639 expression promotes gastric cancer proliferation and metastasis by sponging miR-224-5p and upregulating USP3. Gene. 2020;750:7.

    Article  Google Scholar 

  40. ** GH, Zhang JG, Cao TT, Chen B, Tian Y, Shi Y. Exosome-mediated lncRNA SND1-IT1 from gastric cancer cells enhances malignant transformation of gastric mucosa cells via up-regulating SNAIL1. J Transl Med. 2022;20:18.

    Article  Google Scholar 

  41. Lin KY. Clinical impact and carcinogenic mechanism of USP3 overexpression in gastric cancer. Ann Oncol. 2016;27:1.

    Article  Google Scholar 

  42. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ Br Med J. 2021;374:9.

    Google Scholar 

  43. Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70:299–312.

    Article  PubMed  Google Scholar 

  44. Ohgaki H, Kleihues P. The Definition of Primary and Secondary Glioblastoma. Clin Cancer Res. 2013;19:764–72.

    Article  CAS  PubMed  Google Scholar 

  45. Fan LG, Chen ZX, Wu XT, Cai XM, Feng S, Lu JC, et al. Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial-Mesenchymal Transition via Stabilizing Snail. Mol Cancer Res. 2019;17:1975–84.

    Article  CAS  PubMed  Google Scholar 

  46. Chen WH, Li QY, Zhang GL, Wang H, Zhu ZH, Chen LK. LncRNA HOXA-AS3 promotes the malignancy of glioblastoma through regulating miR-455-5p/USP3 axis. J Cell Mol Med. 2020;24:11755–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nat Rev Dis Prim. 2016;2:21.

    Google Scholar 

  48. Anderson J, Majzner RG, Sondel PM. Immunotherapy of Neuroblastoma: Facts and Hopes. Clin Cancer Res. 2022;28:3196–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rickman DS, Schulte JH, Eilers M. The Expanding World of N-MYC-Driven Tumors. Cancer Discov. 2018;8:150–63.

    Article  CAS  PubMed  Google Scholar 

  50. Nagy Z, Seneviratne JA, Kanikevich M, Chang W, Mayoh C, Venkat P, et al. An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability. Nat Commun. 2021;12:20.

    Article  Google Scholar 

  51. Lunyak VV, Rosenfeld MG. No rest for REST: REST/NRSF regulation of neurogenesis. Cell. 2005;121:499–501.

    Article  CAS  PubMed  Google Scholar 

  52. Karapurkar JK, Kim MS, Colaco JC, Suresh B, Sarodaya N, Kim DH, et al. CRISPR/Cas9-based genome-wide screening of the deubiquitinase subfamily identifies USP3 as a protein stabilizer of REST blocking neuronal differentiation and promotes neuroblastoma tumorigenesis. J Exp Clin Cancer Res. 2023;42:21.

    Article  Google Scholar 

  53. Schuster V, Kreth HW. Nasopharyngeal carcinoma. N Engl J Med. 1992;326:1291.

    Article  CAS  PubMed  Google Scholar 

  54. Wong KCW, Hui EP, Lo KW, Lam WKJ, Johnson D, Li LL, et al. Nasopharyngeal carcinoma: an evolving paradigm. Nat Rev Clin Oncol. 2021;18:679–95.

    Article  CAS  PubMed  Google Scholar 

  55. Zhao WG, **n L, Tang L, Li YJ, Li XQ, Liu RF. A positive feedback loop between LINC01605 and NF-kappa B pathway promotes tumor growth in nasopharyngeal carcinoma. RNA Biol. 2022;19:482–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Feo CF, Ginesu GC, Fancellu A, Perra T, Ninniri C, Deiana G, et al. Current management of incidental gallbladder cancer: A review. Int J Surg. 2022;98:7.

    Article  Google Scholar 

  57. Liang R-P, Zhang X-X, Zhao J, Zhu R-T, Wang W-J, Lu Q-W, et al. Ubiquitin-specific protease 3 facilitates cell proliferation by deubiquitinating pyruvate kinase L/R in gallbladder cancer. Lab Investig. 2022;102:1367–76.

    Article  CAS  PubMed  Google Scholar 

  58. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.

    Article  CAS  PubMed  Google Scholar 

  59. Liao XH, Wang Y, Zhong B, Zhu SY. USP3 promotes proliferation of non-small cell lung cancer through regulating RBM4. Eur Rev Med Pharm Sci. 2020;24:3143–50.

    Google Scholar 

  60. Morgan E, Soerjomataram I, Rumgay H, Coleman HG, Thrift AP, Vignat J, et al. The Global Landscape of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and Projections to 2040: New Estimates From GLOBOCAN 2020. Gastroenterology. 2022;163:649.

    Article  PubMed  Google Scholar 

  61. Abnet CC, Arnold M, Wei WQ. Epidemiology of Esophageal Squamous Cell Carcinoma. Gastroenterology. 2018;154:360–73.

    Article  PubMed  Google Scholar 

  62. Shi K, Zhang JZ, Yang L, Li NN, Yue Y, Du XH, et al. Protein deubiquitylase USP3 stabilizes Aurora A to promote proliferation and metastasis of esophageal squamous cell carcinoma. BMC Cancer. 2021;21:13.

    Article  Google Scholar 

  63. Harbeck N, Gnant M. Breast cancer. Lancet. 2017;389:1134–50.

    Article  PubMed  Google Scholar 

  64. Wu YY, Qin JY, Li FB, Yang CY, Li Z, Zhou ZM, et al. USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5. J Biol Chem. 2019;294:17837–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chae YC, Jung H, Kim JY, Lee DH, Seo SB. Ubiquitin-specific peptidase 3 induces TPA-mediated leukemia cell differentiation via regulating H2AK119ub. Anim Cells Syst. 2019;23:311–7.

    Article  CAS  Google Scholar 

  66. Wong SH, Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol. 2019;16:690–704.

    Article  CAS  PubMed  Google Scholar 

  67. Wang ZZ, Yang J, Di JB, Cui M, **ng JD, Wu F, et al. Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer. Sci Rep. 2017;7:14.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer. J Clin Oncol. 2023;41:3461–8.

    Article  PubMed  Google Scholar 

  69. Zheng ZJ, Wu M, Li HY, Xu WX, Yang MX, Pan KL, et al. Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis. BMC Med. 2023;21:16.

    Article  Google Scholar 

  70. Alkhizzi B, Khan MI, Al-Ghafari A, Choudhry H. Upregulation of circular and linear METTL3 and USP3 in colorectal cancer. Oncol Lett. 2021;22:9.

    Article  Google Scholar 

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Acknowledgements

We would like to acknowledge the reviewers for their helpful comments on this paper.

Funding

This study was supported by the Major Program of the National Natural Science Foundation of China (62227803), the National Natural Science Foundation of China (62141109), the Foreword Leading Technology Fundamental Research Project of Jiangsu (BK20212012), and Jiangsu Province Social Development Project (BE2022812).

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  1. These authors contributed equally: Yizhu Wang, Yanlong Shi, Kaiyi Niu, Rui Yang.

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  1. Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nan**g Medical University, Nan**g, Jiangsu, 210003, China

    Yizhu Wang, Yanlong Shi, Kaiyi Niu, Rui Yang, Qingpeng Lv, Wenning Zhang, Kun Feng & Yewei Zhang

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YS proposed and conceived the outline; RY searched the literatures; YW wrote the original manuscript; KN contributed to the figures; QL provided the tables; KF polished the manuscript; WZ revised and edited the manuscript. All authors read and approved the final manuscript.

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Wang, Y., Shi, Y., Niu, K. et al. Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases. Cell Death Discov. 10, 243 (2024). https://doi.org/10.1038/s41420-024-02010-6

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