Skip to main content

Advertisement

SpringerLink
Log in

E3 ubiquitin ligases in nasopharyngeal carcinoma and implications for therapies

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most common squamous cell carcinomas of the head and neck, and Epstein-Barr virus (EBV) infection is one of the pathogenic factors involved in the oncogenetic development and progression of NPC. E3 ligases, which are key members of the ubiquitin proteasome system (UPS), specifically recognize various oncogenic factors and tumor suppressors and contribute to determining their fate through ubiquitination. Several studies have demonstrated that E3 ligases are aberrantly expressed and mutated in NPC and that these changes are closely associated with the occurrence and progression of NPC. Herein, we aim to thoroughly review the specific action mechanisms by which E3 ligases participate in NPC signaling pathways and discuss their functional relationship with EBV. Moreover, we describe the current progress in and limitations for targeted therapies against E3 ligases in NPC.

Key messages

• E3 ubiquitin ligases, as members of the UPS system, determine the fate of their substrates and may act either as oncogenic or anti-tumorigenic factors in NPC.

• Mutations or dysregulated expression of E3 ubiquitin ligases is closely related to the occurrence, development, and therapeutic sensitivity of NPC, as they play important roles in several signaling pathways affected by EBV infection.

• As promising therapeutic targets, E3 ligases may open new avenues for treatment and for improving the prognosis of NPC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Zhu QY, Zhao GX, Li Y, Talakatta G, Mai HQ, Le QT, Young LS, Zeng MS (2021) Advances in pathogenesis and precision medicine for nasopharyngeal carcinoma. MedComm 2:175–206. https://doi.org/10.1002/mco2.32

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J (2019) Nasopharyngeal carcinoma. Lancet (London, England) 394:64–80. https://doi.org/10.1016/s0140-6736(19)30956-0

    Article  PubMed  Google Scholar 

  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clinicians 68: 394–424. https://doi.org/10.3322/caac.21492

  4. Yang J, Han J, He J, Duan B, Gou Q, Ai P, Liu L, Li Y, Ren K, Wang F et al (2020) Real-world cost-effectiveness analysis of gemcitabine and cisplatin compared to docetaxel and cisplatin plus fluorouracil induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Front Oncol 10:594756. https://doi.org/10.3389/fonc.2020.594756

  5. Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, Chan AT, Huang PY, Benhamou E, Zhu G et al (2015) Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 16:645–655. https://doi.org/10.1016/s1470-2045(15)70126-9

    Article  PubMed  Google Scholar 

  6. Lee AW, Ma BB, Ng WT, Chan AT (2015) Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol : Official J Am Soc Clin Oncol 33:3356–3364. https://doi.org/10.1200/jco.2015.60.9347

    Article  Google Scholar 

  7. Leong YH, Soon YY, Lee KM, Wong LC, Tham IWK, Ho FCH (2018) Long-term outcomes after reirradiation in nasopharyngeal carcinoma with intensity-modulated radiotherapy: a meta-analysis. Head Neck 40:622–631. https://doi.org/10.1002/hed.24993

    Article  PubMed  Google Scholar 

  8. Almobarak AA, Jebreel AB, Abu-Zaid A (2019) Molecular targeted therapy in the management of recurrent and metastatic nasopharyngeal carcinoma: a comprehensive literature review. Cureus 11:e4210. https://doi.org/10.7759/cureus.4210

  9. Mansour MA (2018) Ubiquitination: friend and foe in cancer. Int J Biochem Cell Biol 101:80–93. https://doi.org/10.1016/j.biocel.2018.06.001

    Article  CAS  PubMed  Google Scholar 

  10. Snyder NA, Silva GM (2021) Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response. J Biol Chem 297:101077. https://doi.org/10.1016/j.jbc.2021.101077

  11. Hochstrasser M (1995) Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol 7:215–223. https://doi.org/10.1016/0955-0674(95)80031-x

    Article  CAS  PubMed  Google Scholar 

  12. Bennett EJ, Harper JW (2008) DNA damage: ubiquitin marks the spot. Nat Struct Mol Biol 15:20–22. https://doi.org/10.1038/nsmb0108-20

    Article  CAS  PubMed  Google Scholar 

  13. Chen ZJ, Sun LJ (2009) Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33:275–286. https://doi.org/10.1016/j.molcel.2009.01.014

    Article  CAS  PubMed  Google Scholar 

  14. Metzger MB, Pruneda JN, Klevit RE, Weissman AM (2014) RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochem Biophys Acta 1843:47–60. https://doi.org/10.1016/j.bbamcr.2013.05.026

    Article  CAS  PubMed  Google Scholar 

  15. Hoeller D, Dikic I (2009) Targeting the ubiquitin system in cancer therapy. Nature 458:438–444. https://doi.org/10.1038/nature07960

    Article  CAS  PubMed  Google Scholar 

  16. Morreale FE, Walden H (2016) Types of ubiquitin ligases. Cell 165:248-248.e241. https://doi.org/10.1016/j.cell.2016.03.003

    Article  CAS  PubMed  Google Scholar 

  17. Petroski MD, Deshaies RJ (2005) Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6:9–20. https://doi.org/10.1038/nrm1547

    Article  CAS  PubMed  Google Scholar 

  18. Shimizu K, Nihira NT, Inuzuka H, Wei W (2018) Physiological functions of FBW7 in cancer and metabolism. Cell Signal 46:15–22. https://doi.org/10.1016/j.cellsig.2018.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hussain M, Lu Y, Liu YQ, Su K, Zhang J, Liu J, Zhou GB (2016) Skp1: implications in cancer and SCF-oriented anti-cancer drug discovery. Pharmacol Res 111:34–42. https://doi.org/10.1016/j.phrs.2016.05.027

    Article  CAS  PubMed  Google Scholar 

  20. Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW (2004) Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev 18:2573–2580. https://doi.org/10.1101/gad.1255304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Micale L, Chaignat E, Fusco C, Reymond A, Merla G (2012) The tripartite motif: structure and function. Adv Exp Med Biol 770:11–25

    Article  CAS  PubMed  Google Scholar 

  22. Park HH (2018) Structure of TRAF family: current understanding of receptor recognition. Front Immunol 9:1999. https://doi.org/10.3389/fimmu.2018.01999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Weber J, Polo S, Maspero E (2019) HECT E3 ligases: a tale with multiple facets. Front Physiol 10:370. https://doi.org/10.3389/fphys.2019.00370

    Article  PubMed  PubMed Central  Google Scholar 

  24. Huibregtse JM, Scheffner M, Beaudenon S, Howley PM (1995) A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 92:2563–2567. https://doi.org/10.1073/pnas.92.7.2563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sluimer J, Distel B (2018) Regulating the human HECT E3 ligases. Cellular and molecular life sciences : CMLS 75:3121–3141. https://doi.org/10.1007/s00018-018-2848-2

    Article  CAS  PubMed  Google Scholar 

  26. Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10:398–409. https://doi.org/10.1038/nrm2690

    Article  CAS  PubMed  Google Scholar 

  27. Wang Y, Argiles-Castillo D, Kane EI, Zhou A, Spratt DE (2020) HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance. J Cell Sci 133. https://doi.org/10.1242/jcs.228072

  28. Lorenz S (2018) Structural mechanisms of HECT-type ubiquitin ligases. Biol Chem 399:127–145. https://doi.org/10.1515/hsz-2017-0184

    Article  CAS  PubMed  Google Scholar 

  29. Hatakeyama S, Nakayama KI (2003) U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun 302:635–645. https://doi.org/10.1016/s0006-291x(03)00245-6

    Article  CAS  PubMed  Google Scholar 

  30. Vander Kooi CW, Ohi MD, Rosenberg JA, Oldham ML, Newcomer ME, Gould KL, Chazin WJ (2006) The Prp19 U-box crystal structure suggests a common dimeric architecture for a class of oligomeric E3 ubiquitin ligases. Biochemistry 45:121–130. https://doi.org/10.1021/bi051787e

    Article  CAS  PubMed  Google Scholar 

  31. Murata S, Chiba T, Tanaka K (2003) CHIP: a quality-control E3 ligase collaborating with molecular chaperones. Int J Biochem Cell Biol 35:572–578. https://doi.org/10.1016/s1357-2725(02)00394-1

    Article  CAS  PubMed  Google Scholar 

  32. Sarkar S, Brautigan DL, Larner JM (2017) Aurora kinase A promotes AR degradation via the E3 ligase CHIP. Mol Cancer Res: MCR 15:1063–1072. https://doi.org/10.1158/1541-7786.Mcr-17-0062

    Article  CAS  PubMed  Google Scholar 

  33. Smit JJ, Sixma TK (2014) RBR E3-ligases at work. EMBO Rep 15:142–154. https://doi.org/10.1002/embr.201338166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dove KK, Klevit RE (2017) RING-between-RING E3 ligases: emerging themes amid the variations. J Mol Biol 429:3363–3375. https://doi.org/10.1016/j.jmb.2017.08.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang P, Dai X, Jiang W, Li Y, Wei W (2020) RBR E3 ubiquitin ligases in tumorigenesis. Semin Cancer Biol 67:131–144. https://doi.org/10.1016/j.semcancer.2020.05.002

    Article  CAS  PubMed  Google Scholar 

  36. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204. https://doi.org/10.1016/j.ctrv.2003.07.007

    Article  CAS  PubMed  Google Scholar 

  37. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science (New York, NY) 296:1655–1657. https://doi.org/10.1126/science.296.5573.1655

    Article  CAS  Google Scholar 

  38. Gagliardi PA, Puliafito A, Primo L (2018) PDK1: at the crossroad of cancer signaling pathways. Semin Cancer Biol 48:27–35. https://doi.org/10.1016/j.semcancer.2017.04.014

    Article  CAS  PubMed  Google Scholar 

  39. Wang W, Wen Q, Xu L, Xie G, Li J, Luo J, Chu S, Shi L, Huang D, Li J et al (2014) Activation of Akt/mTOR pathway is associated with poor prognosis of nasopharyngeal carcinoma. PloS One 9:e106098. https://doi.org/10.1371/journal.pone.0106098

  40. Fan X, Xie X, Yang M, Wang Y, Wu H, Deng T, Weng X, Wen W, Nie G (2021) YBX3 mediates the metastasis of nasopharyngeal carcinoma via PI3K/AKT signaling. Front Oncol 11:617621. https://doi.org/10.3389/fonc.2021.617621

  41. Pan S, Liang S, Wang X (2021) ADORA1 promotes nasopharyngeal carcinoma cell progression through regulation of PI3K/AKT/GSK-3β/β-catenin signaling. Life Sci 278:119581. https://doi.org/10.1016/j.lfs.2021.119581

  42. Zheng ZQ, Li ZX, Zhou GQ, Lin L, Zhang LL, Lv JW, Huang XD, Liu RQ, Chen F, He XJ et al (2019) Long noncoding RNA FAM225A promotes nasopharyngeal carcinoma tumorigenesis and metastasis by acting as ceRNA to sponge miR-590-3p/miR-1275 and upregulate ITGB3. Can Res 79:4612–4626. https://doi.org/10.1158/0008-5472.Can-19-0799

    Article  CAS  Google Scholar 

  43. Vaupel P, Schmidberger H, Mayer A (2019) The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol 95:912–919. https://doi.org/10.1080/09553002.2019.1589653

    Article  CAS  PubMed  Google Scholar 

  44. Asmamaw MD, Liu Y, Zheng YC, Shi XJ, Liu HM (2020) Skp2 in the ubiquitin-proteasome system: a comprehensive review. Med Res Rev 40:1920–1949. https://doi.org/10.1002/med.21675

    Article  CAS  PubMed  Google Scholar 

  45. Agrawal Y, Sharma T, Islam S, Nadkarni KS, Santra MK (2022) F-box protein FBXO41 suppresses breast cancer growth by inducing autophagic cell death through facilitating proteasomal degradation of oncogene SKP2. Int J Biochem Cell B 147:106228. https://doi.org/10.1016/j.biocel.2022.106228

  46. Yu X, Zhou L, Liu W, Liu L, Gao F, Li W, Liu H (2022) Skp2 stabilizes Mcl-1 and confers radioresistance in colorectal cancer. Cell Death Dis 13:249. https://doi.org/10.1038/s41419-022-04685-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen M, Lingadahalli S, Narwade N, Lei KMK, Liu S, Zhao Z, Zheng Y, Lu Q, Tang AHN, Poon TCW et al (2022) TRIM33 drives prostate tumor growth by stabilizing androgen receptor from Skp2-mediated degradation. EMBO Rep 23:e53468. https://doi.org/10.15252/embr.202153468

  48. Ji Y, Yang S, Yan X, Zhu L, Yang W, Yang X, Yu F, Shi L, Zhu X, Lu Y et al (2021) CircCRIM1 promotes hepatocellular carcinoma proliferation and angiogenesis by sponging miR-378a-3p and regulating SKP2 expression. Front Cell Dev Biol 9:796686. https://doi.org/10.3389/fcell.2021.796686

  49. Xu HM, Liang Y, Chen Q, Wu QN, Guo YM, Shen GP, Zhang RH, He ZW, Zeng YX, Xie FY et al (2011) Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China. Chin J Cancer 30:204–212. https://doi.org/10.5732/cjc.010.10403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang J, Huang Y, Guan Z, Zhang JL, Su HK, Zhang W, Yue CF, Yan M, Guan S, Liu QQ (2014) E3-ligase Skp2 predicts poor prognosis and maintains cancer stem cell pool in nasopharyngeal carcinoma. Oncotarget 5:5591–5601. https://doi.org/10.18632/oncotarget.2149

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fang FM, Chien CY, Li CF, Shiu WY, Chen CH, Huang HY (2009) Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 73:202–207. https://doi.org/10.1016/j.ijrobp.2008.04.008

    Article  CAS  PubMed  Google Scholar 

  52. Yu X, Wang R, Zhang Y, Zhou L, Wang W, Liu H, Li W (2019) Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin. Oncogene 38:7457–7472. https://doi.org/10.1038/s41388-019-0955-7

    Article  CAS  PubMed  Google Scholar 

  53. Zhang T, Yu GD, Ye HP, Jin Y (2020) TRPP2 promotes the proliferation of nasopharyngeal carcinoma through upregulating Skp2/c-Myc. Eur Rev Med Pharmacol Sci 24:8001–8007. https://doi.org/10.26355/eurrev_202008_22483

    Article  CAS  PubMed  Google Scholar 

  54. Feng S, Wang Y, Zhang R, Yang G, Liang Z, Wang Z, Zhang G (2017) Curcumin exerts its antitumor activity through regulation of miR-7/Skp2/p21 in nasopharyngeal carcinoma cells. Onco Targets Ther 10:2377–2388. https://doi.org/10.2147/ott.S130055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Welcker M, Clurman BE (2008) FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer 8:83–93. https://doi.org/10.1038/nrc2290

    Article  CAS  PubMed  Google Scholar 

  56. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J et al (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science (New York, NY) 333:1154–1157. https://doi.org/10.1126/science.1206923

    Article  CAS  Google Scholar 

  57. Xiao L, Hu ZY, Dong X, Tan Z, Li W, Tang M, Chen L, Yang L, Tao Y, Jiang Y et al (2014) Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene 33:4568–4578. https://doi.org/10.1038/onc.2014.32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang P, Shao Y, Quan F, Liu L, Yang J (2021) FBP1 enhances the radiosensitivity by suppressing glycolysis via the FBXW7/mTOR axis in nasopharyngeal carcinoma cells. Life Sci 283:119840. https://doi.org/10.1016/j.lfs.2021.119840

  59. Wu H, Arron JR (2003) TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. BioEssays: news and reviews in molecular, cellular and developmental biology 25:1096–1105. https://doi.org/10.1002/bies.10352

  60. Li J, Liu N, Tang L, Yan B, Chen X, Zhang J, Peng C (2020) The relationship between TRAF6 and tumors. Cancer Cell Int 20:429. https://doi.org/10.1186/s12935-020-01517-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang J, Wu X, Jiang M, Tai G (2020) Mechanism by which TRAF6 participates in the immune regulation of autoimmune diseases and cancer. Biomed Res Int 2020:4607197. https://doi.org/10.1155/2020/4607197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang Z, Liu Y, Huang S, Fang M (2018) TRAF6 interacts with and ubiquitinates PIK3CA to enhance PI3K activation. FEBS Lett 592:1882–1892. https://doi.org/10.1002/1873-3468.13080

    Article  CAS  PubMed  Google Scholar 

  63. Zou Y, Yang R, Huang ML, Kong YG, Sheng JF, Tao ZZ, Gao L, Chen SM (2019) NOTCH2 negatively regulates metastasis and epithelial-mesenchymal transition via TRAF6/AKT in nasopharyngeal carcinoma. J Exp Clin Cancer Res : CR 38:456. https://doi.org/10.1186/s13046-019-1463-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu Y, Jiang Q, Liu X, Lin X, Tang Z, Liu C, Zhou J, Zhao M, Li X, Cheng Z et al (2019) Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway. EBioMedicine 48:386–404. https://doi.org/10.1016/j.ebiom.2019.08.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Delker RK, Zhou Y, Strikoudis A, Stebbins CE, Papavasiliou FN (2013) Solubility-based genetic screen identifies RING finger protein 126 as an E3 ligase for activation-induced cytidine deaminase. Proc Natl Acad Sci USA 110:1029–1034. https://doi.org/10.1073/pnas.1214538110

    Article  PubMed  Google Scholar 

  66. Rodrigo-Brenni MC, Gutierrez E, Hegde RS (2014) Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Mol Cell 55:227–237. https://doi.org/10.1016/j.molcel.2014.05.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang S, Wang T, Wang L, Zhong L, Li K (2020) Overexpression of RNF126 promotes the development of colorectal cancer via enhancing p53 ubiquitination and degradation. Onco Targets Ther 13:10917–10929. https://doi.org/10.2147/ott.S271855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhi X, Zhao D, Wang Z, Zhou Z, Wang C, Chen W, Liu R, Chen C (2013) E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. Can Res 73:385–394. https://doi.org/10.1158/0008-5472.Can-12-0562

    Article  CAS  Google Scholar 

  69. Yu C, Xue B, Li J, Zhang Q (2022) Tumor cell-derived exosome RNF126 affects the immune microenvironment and promotes nasopharyngeal carcinoma progression by regulating PTEN ubiquitination. Apoptosis: Int J Program Cell Death 27:590–605. https://doi.org/10.1007/s10495-022-01738-9

  70. Hong SW, Jin DH, Shin JS, Moon JH, Na YS, Jung KA, Kim SM, Kim JC, Kim KP, Hong YS et al (2012) Ring finger protein 149 is an E3 ubiquitin ligase active on wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF). J Biol Chem 287:24017–24025. https://doi.org/10.1074/jbc.M111.319822

    Article  CAS  PubMed  Google Scholar 

  71. Nair VS, Gevaert O, Davidzon G, Napel S, Graves EE, Hoang CD, Shrager JB, Quon A, Rubin DL, Plevritis SK (2012) Prognostic PET 18F-FDG uptake imaging features are associated with major oncogenomic alterations in patients with resected non-small cell lung cancer. Can Res 72:3725–3734. https://doi.org/10.1158/0008-5472.Can-11-3943

    Article  CAS  Google Scholar 

  72. Winter JM, Curry NL, Gildea DM, Williams KA, Lee M, Hu Y, Crawford NPS (2018) Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans. BMC Genomics 19:450. https://doi.org/10.1186/s12864-018-4827-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B (2019) The relation between PI3K/AKT signalling pathway and cancer. Gene 698:120–128. https://doi.org/10.1016/j.gene.2019.02.076

    Article  CAS  PubMed  Google Scholar 

  74. Yang H, Qin G, Luo Z, Kong X, Gan C, Zhang R, Jiang W (2022) MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2. Cell Death Dis 13:332. https://doi.org/10.1038/s41419-022-04793-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Thien CB, Langdon WY (2001) Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2:294–307. https://doi.org/10.1038/35067100

    Article  CAS  PubMed  Google Scholar 

  76. Daniels SR, Liyasova M, Kales SC, Nau MM, Ryan PE, Green JE, Lipkowitz S (2019) Loss of function Cbl-c mutations in solid tumors. PloS One 14:e0219143. https://doi.org/10.1371/journal.pone.0219143

  77. Feng J, Lu SS, Xiao T, Huang W, Yi H, Zhu W, Fan S, Feng XP, Li JY, Yu ZZ et al (2020) ANXA1 binds and stabilizes EphA2 to promote nasopharyngeal carcinoma growth and metastasis. Can Res 80:4386–4398. https://doi.org/10.1158/0008-5472.Can-20-0560

    Article  CAS  Google Scholar 

  78. Hoesel B, Schmid JA (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 12:86. https://doi.org/10.1186/1476-4598-12-86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hayden MS, Ghosh S (2012) NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203–234. https://doi.org/10.1101/gad.183434.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ngan HL, Wang L, Lo KW, Lui VWY (2018) Genomic landscapes of EBV-associated nasopharyngeal carcinoma vs. HPV-associated head and neck cancer. Cancers 10. https://doi.org/10.3390/cancers10070210

  81. Campion NJ, Ally M, Jank BJ, Ahmed J, Alusi G (2021) The molecular march of primary and recurrent nasopharyngeal carcinoma. Oncogene 40:1757–1774. https://doi.org/10.1038/s41388-020-01631-2

    Article  CAS  PubMed  Google Scholar 

  82. Jin X, Ma YC, Zhu WY, Fan L (2019) CUL4A expression is associated with tumor stage and prognosis in nasopharyngeal carcinoma. Medicine 98:e18036. https://doi.org/10.1097/md.0000000000018036

  83. Sun X, Zhou J, Zhang Z (2022) Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma. Bioengineered 13:8712–8723. https://doi.org/10.1080/21655979.2022.2054756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yang D, Liang T, Gu Y, Zhao Y, Shi Y, Zuo X, Cao Q, Yang Y, Kan Q (2016) Protein N-arginine methyltransferase 5 promotes the tumor progression and radioresistance of nasopharyngeal carcinoma. Oncol Rep 35:1703–1710. https://doi.org/10.3892/or.2015.4513

    Article  CAS  PubMed  Google Scholar 

  85. Eisenberg I, Hochner H, Levi T, Yelin R, Kahan T, Mitrani-Rosenbaum S (2002) Cloning and characterization of a novel human gene RNF38 encoding a conserved putative protein with a RING finger domain. Biochem Biophys Res Commun 294:1169–1176. https://doi.org/10.1016/s0006-291x(02)00584-3

    Article  CAS  PubMed  Google Scholar 

  86. Peng R, Zhang PF, Yang X, Wei CY, Huang XY, Cai JB, Lu JC, Gao C, Sun HX, Gao Q et al (2019) Overexpression of RNF38 facilitates TGF-β signaling by ubiquitinating and degrading AHNAK in hepatocellular carcinoma. J Exp Clin Cancer Res : CR 38:113. https://doi.org/10.1186/s13046-019-1113-3

    Article  PubMed  PubMed Central  Google Scholar 

  87. Guo WL, Li N, Ma JL, Chen XM, Shi FY (2020) Inhibiting microRNA-301b suppresses cell growth and targets RNF38 in cervical carcinoma. Kaohsiung J Med Sci 36:878–884. https://doi.org/10.1002/kjm2.12273

    Article  CAS  PubMed  Google Scholar 

  88. Lo KW, Huang DP (2002) Genetic and epigenetic changes in nasopharyngeal carcinoma. Semin Cancer Biol 12:451–462. https://doi.org/10.1016/s1044579x02000883

    Article  CAS  PubMed  Google Scholar 

  89. Lin C, Zong J, Lin W, Wang M, Xu Y, Zhou R, Lin S, Guo Q, Chen H, Ye Y et al (2018) EBV-miR-BART8-3p induces epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma cells through activating NF-κB and Erk1/2 pathways. J Exp Clin Cancer Res : CR 37:283. https://doi.org/10.1186/s13046-018-0953-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lin C, Li M, Lin N, Zong J, Pan J, Ye Y (2022) RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma. BMC Cancer 22:549. https://doi.org/10.1186/s12885-022-09641-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ma A, Malynn BA (2012) A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12:774–785. https://doi.org/10.1038/nri3313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. He JQ, Oganesyan G, Saha SK, Zarnegar B, Cheng G (2007) TRAF3 and its biological function. Adv Exp Med Biol 597:48–59. https://doi.org/10.1007/978-0-387-70630-6_4

    Article  PubMed  Google Scholar 

  93. Bishop GA, Stunz LL, Hostager BS (2018) TRAF3 as a multifaceted regulator of B lymphocyte survival and activation. Front Immunol 9:2161. https://doi.org/10.3389/fimmu.2018.02161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shembade N, Harhaj EW (2012) Regulation of NF-κB signaling by the A20 deubiquitinase. Cell Mol Immunol 9:123–130. https://doi.org/10.1038/cmi.2011.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chung GT, Lou WP, Chow C, To KF, Choy KW, Leung AW, Tong CY, Yuen JW, Ko CW, Yip TT et al (2013) Constitutive activation of distinct NF-κB signals in EBV-associated nasopharyngeal carcinoma. J Pathol 231:311–322. https://doi.org/10.1002/path.4239

    Article  CAS  PubMed  Google Scholar 

  96. Li YY, Chung GT, Lui VW, To KF, Ma BB, Chow C, Woo JK, Yip KY, Seo J, Hui EP et al (2017) Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations. Nat Commun 8:14121. https://doi.org/10.1038/ncomms14121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zheng Z, Qu JQ, Yi HM, Ye X, Huang W, Xiao T, Li JY, Wang YY, Feng J, Zhu JF et al (2017) MiR-125b regulates proliferation and apoptosis of nasopharyngeal carcinoma by targeting A20/NF-κB signaling pathway. Cell Death Dis 8:e2855. https://doi.org/10.1038/cddis.2017.211

  98. Yi M, Cai J, Li J, Chen S, Zeng Z, Peng Q, Ban Y, Zhou Y, Li X, Xiong W et al (2018) Rediscovery of NF-κB signaling in nasopharyngeal carcinoma: how genetic defects of NF-κB pathway interplay with EBV in driving oncogenesis? J Cell Physiol 233:5537–5549. https://doi.org/10.1002/jcp.26410

    Article  CAS  PubMed  Google Scholar 

  99. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480. https://doi.org/10.1016/j.cell.2006.10.018

    Article  CAS  PubMed  Google Scholar 

  100. Yang XZ, Chen XM, Zeng LS, Deng J, Ma L, Jin C, Wang R, Wang MH, Wen YF, Wu XL et al (2020) Rab1A promotes cancer metastasis and radioresistance through activating GSK-3β/Wnt/β-catenin signaling in nasopharyngeal carcinoma. Aging 12:20380–20395. https://doi.org/10.18632/aging.103829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ji Y, Wang M, Li X, Cui F (2019) The long noncoding RNA NEAT1 targets miR-34a-5p and drives nasopharyngeal carcinoma progression via Wnt/β-catenin signaling. Yonsei Med J 60:336–345. https://doi.org/10.3349/ymj.2019.60.4.336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nusse R, Clevers H (2017) Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169:985–999. https://doi.org/10.1016/j.cell.2017.05.016

    Article  CAS  PubMed  Google Scholar 

  103. Tsukiyama T, Koo BK, Hatakeyama S (2021) Post-translational Wnt receptor regulation: is the fog slowly clearing?: the molecular mechanism of RNF43/ZNRF3 ubiquitin ligases is not yet fully elucidated and still controversial. BioEssays: news and reviews in molecular, cellular and developmental biology 43:e2000297. https://doi.org/10.1002/bies.202000297

  104. Zhang L, Dang Y, Wang Y, Fan X (2020) Nucleolar and spindle-associated protein 1 accelerates cellular proliferation and invasion in nasopharyngeal carcinoma by potentiating Wnt/β-catenin signaling via modulation of GSK-3β. J Bioenerg Biomembr 52:441–451. https://doi.org/10.1007/s10863-020-09860-6

    Article  CAS  PubMed  Google Scholar 

  105. Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8:438–449. https://doi.org/10.1038/nrc2396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lu Y, Li X, Liu H, Xue J, Zeng Z, Dong X, Zhang T, Wu G, Yang K, Xu S (2021) β-Trcp and CK1δ-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma. Oncogene 40:1269–1283. https://doi.org/10.1038/s41388-020-01596-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shi H, Sun Y, Ruan H, Ji C, Zhang J, Wu P, Li L, Huang C, Jia Y, Zhang X et al (2021) 3,3′-Diindolylmethane promotes gastric cancer progression via β-TrCP-mediated NF-κB activation in gastric cancer-derived MSCs. Front Oncol 11:603533. https://doi.org/10.3389/fonc.2021.603533

  108. Ma J, Fan Z, Tang Q, Xia H, Zhang T, Bi F (2020) Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer. Cell Death Dis 11:530. https://doi.org/10.1038/s41419-020-2719-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yan Q, Zeng Z, Gong Z, Zhang W, Li X, He B, Song Y, Li Q, Zeng Y, Liao Q et al (2015) EBV-miR-BART10-3p facilitates epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma by targeting BTRC. Oncotarget 6:41766–41782. https://doi.org/10.18632/oncotarget.6155

    Article  PubMed  PubMed Central  Google Scholar 

  110. Mo Y, Wang Y, Wang Y, Deng X, Yan Q, Fan C, Zhang S, Zhang S, Gong Z, Shi L et al (2022) Circular RNA circPVT1 promotes nasopharyngeal carcinoma metastasis via the β-TrCP/c-Myc/SRSF1 positive feedback loop. Mol Cancer 21:192. https://doi.org/10.1186/s12943-022-01659-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tomar D, Singh R (2015) TRIM family proteins: emerging class of RING E3 ligases as regulator of NF-κB pathway. Biol Cell 107:22–40. https://doi.org/10.1111/boc.201400046

    Article  CAS  PubMed  Google Scholar 

  112. Zhang L, Afolabi LO, Wan X, Li Y, Chen L (2020) Emerging roles of tripartite motif-containing family proteins (TRIMs) in eliminating misfolded proteins. Front Cell Dev Biol 8:802. https://doi.org/10.3389/fcell.2020.00802

    Article  PubMed  PubMed Central  Google Scholar 

  113. Hong SJ, Chae H, Lardaro T, Hong S, Kim KS (2008) Trim11 increases expression of dopamine beta-hydroxylase gene by interacting with Phox2b. Biochem Biophys Res Commun 368:650–655. https://doi.org/10.1016/j.bbrc.2008.01.165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen L, Brewer MD, Guo L, Wang R, Jiang P, Yang X (2017) Enhanced degradation of misfolded proteins promotes tumorigenesis. Cell Rep 18:3143–3154. https://doi.org/10.1016/j.celrep.2017.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang R, Li SW, Liu L, Yang J, Huang G, Sang Y (2020) TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple. Oncogenesis 9:45. https://doi.org/10.1038/s41389-020-0229-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Esaki N, Enomoto A, Takagishi M, Mizutani Y, Iida T, Ushida K, Shiraki Y, Mii S, Takahashi M (2020) The Daple-CK1ε complex regulates Dvl2 phosphorylation and canonical Wnt signaling. Biochem Biophys Res Commun 532:406–413. https://doi.org/10.1016/j.bbrc.2020.08.066

    Article  CAS  PubMed  Google Scholar 

  117. Begicevic RR, Falasca M (2017) ABC transporters in cancer stem cells: beyond chemoresistance. Int J Mol Sci 18. https://doi.org/10.3390/ijms18112362

  118. Hao HX, Jiang X, Cong F (2016) Control of Wnt receptor turnover by R-spondin-ZNRF3/RNF43 signaling module and its dysregulation in cancer. Cancers 8. https://doi.org/10.3390/cancers8060054

  119. Qin H, Cai A, Xi H, Yuan J, Chen L (2015) ZnRF3 Induces Apoptosis of gastric cancer cells by antagonizing Wnt and Hedgehog signaling. Cell Biochem Biophys 73:361–367. https://doi.org/10.1007/s12013-015-0607-7

    Article  CAS  PubMed  Google Scholar 

  120. Qiu W, Yang Z, Fan Y, Zheng Q (2016) ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 37:12665–12672. https://doi.org/10.1007/s13277-016-5250-4

    Article  CAS  PubMed  Google Scholar 

  121. Wang Z, Wang Y, Ren H, Jin Y, Guo Y (2017) ZNRF3 inhibits the invasion and tumorigenesis in nasopharyngeal carcinoma cells by inactivating the Wnt/β-catenin pathway. Oncol Res 25:571–577. https://doi.org/10.3727/97818823455816x14760478220149

    Article  PubMed  PubMed Central  Google Scholar 

  122. Wang Z, Wang Y, Ma X, Dang C (2021) RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway. Life Sci 282:119817. https://doi.org/10.1016/j.lfs.2021.119817

  123. Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480. https://doi.org/10.1124/mol.106.027029

    Article  CAS  PubMed  Google Scholar 

  124. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54. https://doi.org/10.1016/s0092-8674(01)00507-4

    Article  CAS  PubMed  Google Scholar 

  125. Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578. https://doi.org/10.1146/annurev.cellbio.15.1.551

    Article  CAS  PubMed  Google Scholar 

  126. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279:38458–38465. https://doi.org/10.1074/jbc.M406026200

    Article  CAS  PubMed  Google Scholar 

  127. Chen Z, Xu XH (2015) Combining antiangiogenic therapy and radiation in nasopharyngeal carcinoma. Saudi Med J 36:659–664. https://doi.org/10.15537/smj.2015.6.11460

    Article  PubMed  PubMed Central  Google Scholar 

  128. Xiang T, Lin YX, Ma W, Zhang HJ, Chen KM, He GP, Zhang X, Xu M, Feng QS, Chen MY et al (2018) Vasculogenic mimicry formation in EBV-associated epithelial malignancies. Nat Commun 9:5009. https://doi.org/10.1038/s41467-018-07308-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Della NG, Senior PV, Bowtell DD (1993) Isolation and characterisation of murine homologues of the Drosophila seven in absentia gene (sina). Development (Cambridge, England) 117:1333–1343. https://doi.org/10.1242/dev.117.4.1333

    Article  CAS  PubMed  Google Scholar 

  130. Gopalsamy A, Hagen T, Swaminathan K (2014) Investigating the molecular basis of Siah1 and Siah2 E3 ubiquitin ligase substrate specificity. PloS One 9:e106547. https://doi.org/10.1371/journal.pone.0106547

  131. Kondo S, Seo SY, Yoshizaki T, Wakisaka N, Furukawa M, Joab I, Jang KL, Pagano JS (2006) EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Can Res 66:9870–9877. https://doi.org/10.1158/0008-5472.Can-06-1679

    Article  CAS  Google Scholar 

  132. Kitagawa N, Kondo S, Wakisaka N, Zen Y, Nakanishi Y, Tsuji A, Endo K, Murono S, Yoshizaki T (2013) Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: novel prognostic factors of nasopharyngeal carcinoma. Cancer Lett 331:52–57. https://doi.org/10.1016/j.canlet.2012.12.002

    Article  CAS  PubMed  Google Scholar 

  133. Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, Yoshizaki T, Pagano JS, Shackelford J (2014) Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene 33:4613–4622. https://doi.org/10.1038/onc.2014.66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tian X, Liu Y, Wang Z, Wu S (2021) miR-144 delivered by nasopharyngeal carcinoma-derived EVs stimulates angiogenesis through the FBXW7/HIF-1α/VEGF-A axis. Mol Ther Nucleic Acids 24:1000–1011. https://doi.org/10.1016/j.omtn.2021.03.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Finlay CA, Hinds PW, Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093. https://doi.org/10.1016/0092-8674(89)90045-7

    Article  CAS  PubMed  Google Scholar 

  136. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9:862–873. https://doi.org/10.1038/nrc2763

    Article  CAS  PubMed  Google Scholar 

  137. Kim MP, Lozano G (2018) Mutant p53 partners in crime. Cell Death Differ 25:161–168. https://doi.org/10.1038/cdd.2017.185

    Article  CAS  PubMed  Google Scholar 

  138. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283. https://doi.org/10.1038/nrm2147

    Article  CAS  PubMed  Google Scholar 

  139. Sun Y, Hegamyer G, Cheng YJ, Hildesheim A, Chen JY, Chen IH, Cao Y, Yao KT, Colburn NH (1992) An infrequent point mutation of the p53 gene in human nasopharyngeal carcinoma. Proc Natl Acad Sci USA 89:6516–6520. https://doi.org/10.1073/pnas.89.14.6516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Sheu LF, Chen A, Lee HS, Hsu HY, Yu DS (2004) Cooperative interactions among p53, bcl-2 and Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma cells. Pathol Int 54:475–485. https://doi.org/10.1111/j.1440-1827.2004.01654.x

    Article  CAS  PubMed  Google Scholar 

  141. Chang KP, Hao SP, Lin SY, Tsao KC, Kuo TT, Tsai MH, Tseng CK, Tsang NM (2002) A lack of association between p53 mutations and recurrent nasopharyngeal carcinomas refractory to radiotherapy. Laryngoscope 112:2015–2019. https://doi.org/10.1097/00005537-200211000-00019

    Article  CAS  PubMed  Google Scholar 

  142. Li L, Li W, Xiao L, Xu J, Chen X, Tang M, Dong Z, Tao Q, Cao Y (2012) Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53. Cell cycle (Georgetown, Tex) 11:2327–2336. https://doi.org/10.4161/cc.20771

    Article  CAS  PubMed  Google Scholar 

  143. Yee-Lin V, Pooi-Fong W, Soo-Beng AK (2018) Nutlin-3, A p53-Mdm2 antagonist for nasopharyngeal carcinoma treatment. Mini Rev Med Chem 18:173–183. https://doi.org/10.2174/1389557517666170717125821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhang P, Li X, He Q, Zhang L, Song K, Yang X, He Q, Wang Y, Hong X, Ma J et al (2020) TRIM21-SERPINB5 aids GMPS repression to protect nasopharyngeal carcinoma cells from radiation-induced apoptosis. J Biomed Sci 27:30. https://doi.org/10.1186/s12929-020-0625-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhao Y, Yu H, Hu W (2014) The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim Biophys Sin 46:180–189. https://doi.org/10.1093/abbs/gmt147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Karni-Schmidt O, Lokshin M, Prives C (2016) The roles of MDM2 and MDMX in cancer. Annu Rev Pathol 11:617–644. https://doi.org/10.1146/annurev-pathol-012414-040349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Li J, Kurokawa M (2015) Regulation of MDM2 stability after DNA damage. J Cell Physiol 230:2318–2327. https://doi.org/10.1002/jcp.24994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhang P, Wu SK, Wang Y, Fan ZX, Li CR, Feng M, Xu P, Wang WD, Lang JY (2015) p53, MDM2, eIF4E and EGFR expression in nasopharyngeal carcinoma and their correlation with clinicopathological characteristics and prognosis: a retrospective study. Oncol Lett 9:113–118. https://doi.org/10.3892/ol.2014.2631

    Article  PubMed  Google Scholar 

  149. Zhang Y, Bai Y, Zhang Y, Guan J, Chen L (2012) The MDM2 309 T/G polymorphism is associated with head and neck cancer risk especially in nasopharyngeal cancer: a meta-analysis. Onkologie 35:666–670. https://doi.org/10.1159/000343639

    Article  CAS  PubMed  Google Scholar 

  150. Sousa H, Pando M, Breda E, Catarino R, Medeiros R (2011) Role of the MDM2 SNP309 polymorphism in the initiation and early age of onset of nasopharyngeal carcinoma. Mol Carcinog 50:73–79. https://doi.org/10.1002/mc.20689

    Article  CAS  PubMed  Google Scholar 

  151. Liu R, Zhou M, Zhang P, Zhao Y, Zhang Y (2020) Cell proliferation and invasion is promoted by circSERPINA3 in nasopharyngeal carcinoma by regulating miR-944/MDM2 axis. J Cancer 11:3910–3918. https://doi.org/10.7150/jca.42799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hwang YC, Lu TY, Huang DY, Kuo YS, Kao CF, Yeh NH, Wu HC, Lin CT (2009) NOLC1, an enhancer of nasopharyngeal carcinoma progression, is essential for TP53 to regulate MDM2 expression. Am J Pathol 175:342–354. https://doi.org/10.2353/ajpath.2009.080931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ozato K, Shin DM, Chang TH, Morse HC 3rd (2008) TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol 8:849–860. https://doi.org/10.1038/nri2413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, Martens JW, Demmers JA, Verrijzer CP (2014) Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell 53:458–470. https://doi.org/10.1016/j.molcel.2013.12.017

    Article  CAS  PubMed  Google Scholar 

  155. Zhang J, Li YQ, Guo R, Wang YQ, Zhang PP, Tang XR, Wen X, Hong XH, Lei Y, He QM et al (2019) Hypermethylation of SHISA3 promotes nasopharyngeal carcinoma metastasis by reducing SGSM1 stability. Can Res 79:747–759. https://doi.org/10.1158/0008-5472.Can-18-1754

    Article  CAS  Google Scholar 

  156. Wang H, Zhou Y, Oyang L, Han Y, Xia L, Lin J, Tang Y, Su M, Tan S, Tian Y et al (2019) LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma. Oncogene 38:5062–5075. https://doi.org/10.1038/s41388-019-0778-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Zhao Y, Li WF, Li QJ, He SW, He QM, Long LF, Liu N, Ma J (2021) WIPI-1 inhibits metastasis and tumour growth via the WIPI-1-TRIM21 axis and MYC regulation in nasopharyngeal carcinoma. Oral Oncol 122:105576. https://doi.org/10.1016/j.oraloncology.2021.105576

  158. Qi YF, Liu M, Zhang Y, Liu W, Xiao H, Luo B (2019) EBV down-regulates COX-2 expression via TRAF2 and ERK signal pathway in EBV-associated gastric cancer. Virus Res 272:197735. https://doi.org/10.1016/j.virusres.2019.197735

  159. Guasparri I, Bubman D, Cesarman E (2008) EBV LMP2A affects LMP1-mediated NF-kappaB signaling and survival of lymphoma cells by regulating TRAF2 expression. Blood 111:3813–3820. https://doi.org/10.1182/blood-2007-03-080309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hagemeier SR, Barlow EA, Kleman AA, Kenney SC (2011) The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent manner. J Virol 85:4318–4329. https://doi.org/10.1128/jvi.01856-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zhu H, Ding W, Wu J, Ma R, Pan Z, Mao X (2020) TRAF2 knockdown in nasopharyngeal carcinoma induced cell cycle arrest and enhanced the sensitivity to radiotherapy. Biomed Res Int 2020:1641340. https://doi.org/10.1155/2020/1641340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zheng MZ, Qin HD, Yu XJ, Zhang RH, Chen LZ, Feng QS, Zeng YX (2007) Haplotype of gene Nedd4 binding protein 2 associated with sporadic nasopharyngeal carcinoma in the Southern Chinese population. J Transl Med 5:36. https://doi.org/10.1186/1479-5876-5-36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Feng S, Yang G, Yang H, Liang Z, Zhang R, Fan Y, Zhang G (2017) NEDD4 is involved in acquisition of epithelial-mesenchymal transition in cisplatin-resistant nasopharyngeal carcinoma cells. Cell cycle (Georgetown, Tex) 16:869–878. https://doi.org/10.1080/15384101.2017.1308617

    Article  CAS  PubMed  Google Scholar 

  164. Courbard JR, Fiore F, Adélaïde J, Borg JP, Birnbaum D, Ollendorff V (2002) Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. J Biol Chem 277:45267–45275. https://doi.org/10.1074/jbc.M206460200

    Article  CAS  PubMed  Google Scholar 

  165. Gay DL, Ramón H, Oliver PM (2008) Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity. Immunol Res 42:51–64. https://doi.org/10.1007/s12026-008-8034-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Gainullin MR, Zhukov IY, Zhou X, Mo Y, Astakhova L, Ernberg I, Matskova L (2017) Degradation of cofilin is regulated by Cbl, AIP4 and Syk resulting in increased migration of LMP2A positive nasopharyngeal carcinoma cells. Sci Rep 7:9012. https://doi.org/10.1038/s41598-017-09540-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Xu J, Huang Y, Zhao J, Wu L, Qi Q, Liu Y, Li G, Li J, Liu H, Wu H (2021) Cofilin: a promising protein implicated in cancer metastasis and apoptosis. Front Cell Dev Biol 9:599065. https://doi.org/10.3389/fcell.2021.599065

  168. Wang L, Sang J, Zhang Y, Gao L, Zhao D, Cao H (2022) Circular RNA ITCH attenuates the progression of nasopharyngeal carcinoma by inducing PTEN upregulation via miR-214. J Genet Med 24:e3391. https://doi.org/10.1002/jgm.3391

  169. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol: Official J Am Soc Clin Oncol 20:4420–4427. https://doi.org/10.1200/jco.2002.01.133

    Article  CAS  Google Scholar 

  170. Dou QP, Zonder JA (2014) Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr Cancer Drug Targets 14:517–536. https://doi.org/10.2174/1568009614666140804154511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Jiang GM, Wang HS, Du J, Ma WF, Wang H, Qiu Y, Zhang QG, Xu W, Liu HF, Liang JP (2017) Bortezomib relieves immune tolerance in nasopharyngeal carcinoma via STAT1 suppression and indoleamine 2,3-dioxygenase downregulation. Cancer Immunol Res 5:42–51. https://doi.org/10.1158/2326-6066.Cir-16-0102

    Article  CAS  PubMed  Google Scholar 

  172. Hui KF, Lam BH, Ho DN, Tsao SW, Chiang AK (2013) Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol Cancer Ther 12:747–758. https://doi.org/10.1158/1535-7163.Mct-12-0811

    Article  CAS  PubMed  Google Scholar 

  173. Hui KF, Chiang AK (2014) Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism. Int J Cancer 135:2950–2961. https://doi.org/10.1002/ijc.28924

    Article  CAS  PubMed  Google Scholar 

  174. Hu L, Pan X, Hu J, Zeng H, Liu X, Jiang M, Jiang B (2021) Proteasome inhibitors decrease paclitaxel‑induced cell death in nasopharyngeal carcinoma with the accumulation of CDK1/cyclin B1. Int J Mol Med 48. https://doi.org/10.3892/ijmm.2021.5026

  175. Benvenuto M, Ciuffa S, Focaccetti C, Sbardella D, Fazi S, Scimeca M, Tundo GR, Barillari G, Segni M, Bonanno E et al (2021) Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells. Sci Rep 11:19051. https://doi.org/10.1038/s41598-021-98450-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Gilbert J, Lee JW, Argiris A, Haigentz M Jr, Feldman LE, Jang M, Arun P, Van Waes C, Forastiere AA (2013) Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): a trial of the Eastern Cooperative Oncology Group. Head Neck 35:942–948. https://doi.org/10.1002/hed.23046

    Article  PubMed  Google Scholar 

  177. Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, Ott M, Mascarenhas J, Andreeff M (2020) MDM2 inhibition: an important step forward in cancer therapy. Leukemia 34:2858–2874. https://doi.org/10.1038/s41375-020-0949-z

    Article  PubMed  Google Scholar 

  178. Lauria A, Tutone M, Ippolito M, Pantano L, Almerico AM (2010) Molecular modeling approaches in the discovery of new drugs for anti-cancer therapy: the investigation of p53-MDM2 interaction and its inhibition by small molecules. Curr Med Chem 17:3142–3154. https://doi.org/10.2174/092986710792232021

    Article  CAS  PubMed  Google Scholar 

  179. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (New York, NY) 303:844–848. https://doi.org/10.1126/science.1092472

    Article  CAS  Google Scholar 

  180. Voon YL, Ahmad M, Wong PF, Husaini R, Ng WT, Leong CO, Lane DP, Khoo AS (2015) Nutlin-3 sensitizes nasopharyngeal carcinoma cells to cisplatin-induced cytotoxicity. Oncol Rep 34:1692–1700. https://doi.org/10.3892/or.2015.4177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Yan M, Qian YM, Yue CF, Wang ZF, Wang BC, Zhang W, Zheng FM, Liu Q (2016) Inhibition of histone deacetylases induces formation of multipolar spindles and subsequent p53-dependent apoptosis in nasopharyngeal carcinoma cells. Oncotarget 7:44171–44184. https://doi.org/10.18632/oncotarget.9922

    Article  PubMed  PubMed Central  Google Scholar 

  182. Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C et al (2013) Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 56:5979–5983. https://doi.org/10.1021/jm400487c

    Article  CAS  PubMed  Google Scholar 

  183. Zanjirband M, Curtin N, Edmondson RJ, Lunec J (2017) Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer. Oncotarget 8:69779–69796. https://doi.org/10.18632/oncotarget.19266

    Article  PubMed  PubMed Central  Google Scholar 

  184. Chen L, Rousseau RF, Middleton SA, Nichols GL, Newell DR, Lunec J, Tweddle DA (2015) Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget 6:10207–10221. https://doi.org/10.18632/oncotarget.3504

    Article  PubMed  PubMed Central  Google Scholar 

  185. Khurana A, Shafer DA (2019) MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther 12:2903–2910. https://doi.org/10.2147/ott.S172315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Fan X, Wang Y, Song J, Wu H, Yang M, Lu L, Weng X, Liu L, Nie G (2019) MDM2 inhibitor RG7388 potently inhibits tumors by activating p53 pathway in nasopharyngeal carcinoma. Cancer Biol Ther 20:1328–1336. https://doi.org/10.1080/15384047.2019.1638677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Chen Y, Zhang R, Zhao W, Lv M, Chen M, Yan Y, Feng S (2019) Paeoniflorin exhibits antitumor effects in nasopharyngeal carcinoma cells through downregulation of NEDD4. Am J Transl Res 11:7579–7590

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Hou R, Liu X, Yang H, Deng S, Cheng C, Liu J, Li Y, Zhang Y, Jiang J, Zhu Z et al (2022) Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis by inducing ENKUR to stabilize p53 expression. Cancer Lett 531:57–70. https://doi.org/10.1016/j.canlet.2022.01.025

    Article  CAS  PubMed  Google Scholar 

  189. Liu L, Yang J, Ji W, Wang C (2019) Curcumin inhibits proliferation of Epstein-Barr virus-associated human nasopharyngeal carcinoma cells by inhibiting EBV nuclear antigen 1 expression. Biomed Res Int 2019:8592921. https://doi.org/10.1155/2019/8592921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Li X, Song Y (2020) Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol 13:50. https://doi.org/10.1186/s13045-020-00885-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS et al (2019) A selective BCL-X(L) PROTAC degrader achieves safe and potent antitumor activity. Nat Med 25:1938–1947. https://doi.org/10.1038/s41591-019-0668-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Zhao Q, Ren C, Liu L, Chen J, Shao Y, Sun N, Sun R, Kong Y, Ding X, Zhang X et al (2019) Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. J Med Chem 62:9281–9298. https://doi.org/10.1021/acs.jmedchem.9b01264

    Article  CAS  PubMed  Google Scholar 

  193. Shi S, Du Y, Huang L, Cui J, Niu J, Xu Y, Zhu Q (2022) Discovery of novel potent covalent inhibitor-based EGFR degrader with excellent in vivo efficacy. Bioorg Chem 120:105605. https://doi.org/10.1016/j.bioorg.2022.105605

  194. Zeng S, Huang W, Zheng X, Liyan C, Zhang Z, Wang J, Shen Z (2021) Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: recent progress and future challenges. Eur J Med Chem 210:112981. https://doi.org/10.1016/j.ejmech.2020.112981

  195. Zhao L, Zhao J, Zhong K, Tong A, Jia D (2022) Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther 7:113. https://doi.org/10.1038/s41392-022-00966-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Fang Y, He Q, Cao J (2022) Targeted protein degradation and regulation with molecular glue: past and recent discoveries. Curr Med Chem 29:2490–2503. https://doi.org/10.2174/0929867328666210806113949

    Article  CAS  PubMed  Google Scholar 

  197. Asatsuma-Okumura T, Ito T, Handa H (2019) Molecular mechanisms of cereblon-based drugs. Pharmacol Ther 202:132–139. https://doi.org/10.1016/j.pharmthera.2019.06.004

    Article  CAS  PubMed  Google Scholar 

  198. Liang L, Liu Z, Zhu H, Wang H, Wei Y, Ning X, Shi Z, Jiang L, Lin Z, Yan H et al (2022) Efficacy and safety of thalidomide in preventing oral mucositis in patients with nasopharyngeal carcinoma undergoing concurrent chemoradiotherapy: a multicenter, open-label, randomized controlled trial. Cancer 128:1467–1474. https://doi.org/10.1002/cncr.34074

    Article  CAS  PubMed  Google Scholar 

  199. Xu G, Wang B, Yang M, Qian W (2015) A rare case of nasopharyngeal carcinoma in a patient with multiple myeloma after treatment by lenalidomide. Int J Clin Exp Pathol 8:15025–15029

    PubMed  PubMed Central  Google Scholar 

  200. Surka C, Jin L, Mbong N, Lu CC, Jang IS, Rychak E, Mendy D, Clayton T, Tindall E, Hsu C et al (2021) CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood 137:661–677. https://doi.org/10.1182/blood.2020008676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Zhao CX, Zhu W, Ba ZQ, Xu HJ, Liu WD, Zhu B, Wang L, Song YJ, Yuan S, Ren CP (2018) The regulatory network of nasopharyngeal carcinoma metastasis with a focus on EBV, lncRNAs and miRNAs. Am J Cancer Res 8:2185–2209

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Kang Y, He W, Ren C, Qiao J, Guo Q, Hu J, Xu H, Jiang X, Wang L (2020) Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma. Signal Transduct Target Ther 5:245. https://doi.org/10.1038/s41392-020-00340-2

    Article  PubMed  PubMed Central  Google Scholar 

  203. Li Y, Liu X, Lin X, Zhao M, Xiao Y, Liu C, Liang Z, Lin Z, Yi R, Tang Z et al (2019) Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9. Signal Transduct Target Ther 4:48. https://doi.org/10.1038/s41392-019-0084-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Gao Q, Tang L, Wu L, Li K, Wang H, Li W, Wu J, Li M, Wang S, Zhao L (2018) LASP1 promotes nasopharyngeal carcinoma progression through negatively regulation of the tumor suppressor PTEN. Cell Death Dis 9:393. https://doi.org/10.1038/s41419-018-0443-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Drummond CJ, Esfandiari A, Liu J, Lu X, Hutton C, Jackson J, Bennaceur K, Xu Q, Makimanejavali AR, Del Bello F et al (2016) TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation. Oncotarget 7:46203–46218. https://doi.org/10.18632/oncotarget.10073

    Article  PubMed  PubMed Central  Google Scholar 

  206. Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G (2017) MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol 10:133. https://doi.org/10.1186/s13045-017-0500-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Anwar Z, Ali MS, Galvano A, Perez A, La Mantia M, Bukhari I, Swiatczak B (2022) PROTACs: the future of leukemia therapeutics. Front Cell Dev Biol 10:851087. https://doi.org/10.3389/fcell.2022.851087

  208. Gong D, Zhu H, Zeng L, Hu R, Hu J, Ding J (2021) Overexpression of HOXA10 promotes the growth and metastasis of nasopharyngeal carcinoma. Exp Biol Med (Maywood) 246:2454–2462. https://doi.org/10.1177/15353702211030854

    Article  CAS  PubMed  Google Scholar 

  209. Song Y, Zhou X, Bai W, Ma X (2015) FBW7 increases drug sensitivity to cisplatin in human nasopharyngeal carcinoma by downregulating the expression of multidrug resistance-associated protein. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36:4197–4202. https://doi.org/10.1007/s13277-015-3056-4

    Article  CAS  PubMed  Google Scholar 

  210. Mai J, Zhong ZY, Guo GF, Chen XX, Xiang YQ, Li X, Zhang HL, Chen YH, Xu XL, Wu RY et al (2019) Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma. Theranostics 9:3541–3554. https://doi.org/10.7150/thno.32908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Zeng R, Tan G, Li W, Ma Y (2018) Increased expression of Cullin 3 in nasopharyngeal carcinoma and knockdown inhibits proliferation and invasion. Oncol Res 26:111–122. https://doi.org/10.3727/096504017x14924753593574

    Article  PubMed  PubMed Central  Google Scholar 

  212. Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, Soria JC, Chawla S, de Weger V, Wagner AJ et al (2020) Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma. Invest New Drugs 38:831–843. https://doi.org/10.1007/s10637-019-00840-1

    Article  CAS  PubMed  Google Scholar 

  213. Takahashi S, Fujiwara Y, Nakano K, Shimizu T, Tomomatsu J, Koyama T, Ogura M, Tachibana M, Kakurai Y, Yamashita T et al (2021) Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: a phase I study. Cancer Sci 112:2361–2370. https://doi.org/10.1111/cas.14875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by The Natural Science Foundation of Ningbo (Grant Nos. 2021J017 and 2021J065), The Public Welfare Science and Technology Program Project of Ningbo (Grant No. 2021S116), The Public Welfare Science and Technology Program Project of Ningbo (Grant No. 202002N3194), The National Natural Science Foundation of China (Grant No. 32270821), and The K.C. Wong Magna Fund of Ningbo University.

Author information

Author notes

  1. Zijian Zhou and Kaifeng Zheng contributed equally to this work.

Authors and Affiliations

  1. Department of Chemoradiotherapy, The Affiliated People’s Hospital of Ningbo University, Ningbo, 315040, China

    Zijian Zhou, Kaifeng Zheng, Jun Chen & Xiaofeng Jin

  2. Department of Otolaryngology-Head and Neck Surgery, The Affiliated People’s Hospital of Ningbo University, Ningbo, 315040, China

    Shao Zhou

  3. Department of Otolaryngology-Head and Neck Surgery, Ningbo Yinzhou Second Hospital, Ningbo, 315199, China

    Youxiong Yang

  4. Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center of Ningbo University, Ningbo, 315211, China

    Xiaofeng Jin

Authors
  1. Zijian Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaifeng Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Youxiong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaofeng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: X. Jin, J. Chen, and Y. Yang; writing, review, and/or revision of the manuscript: Z. Zhou, K. Zheng, S. Zhou, and X. Jin.

Corresponding authors

Correspondence to Youxiong Yang, Jun Chen or Xiaofeng Jin.

Ethics declarations

Ethics approval

Not applicable.

Institutional review board statement

Not applicable.

Informed consent statement

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Z., Zheng, K., Zhou, S. et al. E3 ubiquitin ligases in nasopharyngeal carcinoma and implications for therapies. J Mol Med 101, 1543–1565 (2023). https://doi.org/10.1007/s00109-023-02376-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-023-02376-7

Keywords

Search

Navigation