The role of E3 ubiquitin ligase HECTD3 in cancer and beyond

  • Qiuyun Jiang
  • Fubing Li
  • Zhuo Cheng
  • Yanjie Kong
  • Ceshi ChenEmail author


Ubiquitin modification plays significant roles in protein fate determination, signaling transduction, and cellular processes. Over the past 2 decades, the number of studies on ubiquitination has demonstrated explosive growth. E3 ubiquitin ligases are the key enzymes that determine the substrate specificity and are involved in cancer. Several recent studies shed light on the functions and mechanisms of HECTD3 E3 ubiquitin ligase. This review describes the progress in the recent studies of HECTD3 in cancer and other diseases. We propose that HECTD3 is a potential biomarker and a therapeutic target, and discuss the future directions for HECTD3 investigations.


Ubiquitination HECTD3 Cancer Inhibitors 



Adrenocortical carcinoma


Angiopoietin 1


Breast invasive carcinoma


Breast cancer type 1 susceptibility protein


Abelson murine leukemia viral homolog 1




RAF proto-oncogene serine/threonine-protein kinase


Cullin-RING E3 ubiquitin ligase 7




Cullin 7


DNA-encoded compound libraries


Death-inducing signaling complex


Lymphoid neoplasm diffuse large B-cell lymphoma


Deubiquitinating enzyme


Ubiquitin-activating enzyme


Ubiquitin-conjugating enzyme


Ubiquitin ligase


E6-associated protein


Experimental autoimmune encephalomyelitis


Epithelial cell transforming 2


Epidermal growth factor receptor


Endoplasmic reticulum


Erb-b2 receptor tyrosine kinase 4


Mitogen-activated protein kinase 1


Esophageal squamous cell carcinoma


Fragment-based drug discovery


F-box and WD repeat domain containing 7


Fluorescence polarization assay for high-throughput screening


Homologous to E6AP C terminus


Homologous to the E6-associated protein carboxyl terminus domain containing 3


Erb-b2 receptor tyrosine kinase 2


Hypoxia inducible factor 1 subunit alpha


Heat shock protein 90


High-throughput screening technologies


HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1




Inositol requiring enzyme 1 alpha


Interferon regulatory factor 3


Itchy E3 ubiquitin protein ligase


Kruppel like factor 5


Large tumor suppressor kinase 1


Liver hepatocellular carcinoma


Brain lower grade glioma


Lung adenocarcinoma


MALT1 paracaspase


Myeloid cell leukemia 1


Murine double minute 2




NEDD4 E3 ubiquitin protein ligase


Ovarian serous cystadenocarcinoma




Promyelocytic leukemia protein


Phosphatase and tensin homolog




Really interesting new genes


RCC1 like domain


Ring finger protein 20


Retineic-acid-receptor-related orphan nuclear receptor γ


SKP1-CUL1-F-box protein


S-phase kinase-associated protein 2


SMAD family member 2


SMAD specific E3 ubiquitin protein ligase 2


Signal transducer and activator of transcription 3


Trio-associated repeat on actin


TANK binding kinase 1


Transforming growth factor β


Transforming growth factor β receptor 1


T helper 17


Thyroid carcinoma




Triple negative breast cancer


TNF receptor-associated factor 3


TNF receptor-associated factor 6


TNF-related apoptosis-inducing ligand




Uterine Corpus Endometrial Carcinoma


Uterine Carcinosarcoma


Ub variant


Uterine carcinosarcoma


pVHL-elongin C-elongin B-cullin 2-RBX1


Von Hippel–Lindau disease tumor suppressor


WW domain containing E3 ubiquitin protein ligase 1


WW domain containing E3 ubiquitin protein ligase 2


X-box binding protein 1



This study was supported in part by grants from the National Key R&D Program of China (2018YFC2000400) and the National Nature Science Foundation of China (81830087, U1602221, and 31771516 to Chen, C and 81773149 to Kong Y) and the Shenzhen Municipal Government of China (KQTD20170810160226082).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.


  1. 1.
    Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503–533CrossRefGoogle Scholar
  2. 2.
    Rape M (2018) Ubiquitylation at the crossroads of development and disease. Nat Rev Mol Cell Biol 19(1):59–70. CrossRefPubMedGoogle Scholar
  3. 3.
    Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229. CrossRefPubMedGoogle Scholar
  4. 4.
    Tokunaga F, Sakata S-i, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K (2009) Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nat Cell Biol 11:123.
  5. 5.
    Trempe JF (2011) Reading the ubiquitin postal code. Curr Opin Struct Biol 21(6):792–801. CrossRefPubMedGoogle Scholar
  6. 6.
    Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10(6):398–409. CrossRefPubMedGoogle Scholar
  7. 7.
    Haglund K, Dikic I (2005) Ubiquitylation and cell signaling. EMBO J 24(19):3353–3359. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hoeller D, Hecker CM, Dikic I (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 6(10):776–788. CrossRefPubMedGoogle Scholar
  9. 9.
    Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science (New York, NY) 315(5809):201–205. CrossRefGoogle Scholar
  10. 10.
    Huen MS, Sy SM, Chen J (2010) BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol 11(2):138–148. CrossRefPubMedGoogle Scholar
  11. 11.
    Vucic D, Dixit VM, Wertz IE (2011) Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12(7):439–452. CrossRefPubMedGoogle Scholar
  12. 12.
    Gilberto S, Peter M (2017) Dynamic ubiquitin signaling in cell cycle regulation. J Cell Biol 216(8):2259–2271. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Senft D, Qi J, Ronai ZA (2018) Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18(2):69–88. CrossRefPubMedGoogle Scholar
  14. 14.
    Popovic D, Vucic D, Dikic I (2014) Ubiquitination in disease pathogenesis and treatment. Nat Med 20(11):1242–1253. CrossRefPubMedGoogle Scholar
  15. 15.
    He M, Zhou Z, Wu G, Chen Q, Wan Y (2017) Emerging role of DUBs in tumor metastasis and apoptosis: therapeutic implication. Pharmacol Ther 177:96–107CrossRefGoogle Scholar
  16. 16.
    Harrigan JA, Jacq X, Martin NM, Jackson SP (2018) Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov 17(1):57–78. CrossRefPubMedGoogle Scholar
  17. 17.
    Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung MC, Nakayama KI, Lin HK (2012) The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 149(5):1098–1111. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dubrez L, Rajalingam K (2015) IAPs and cell migration. Semin Cell Dev Biol 39:124–131. CrossRefPubMedGoogle Scholar
  19. 19.
    Kim H, Frederick DT, Levesque MP, Cooper ZA, Feng Y, Krepler C, Brill L, Samuels Y, Hayward NK, Perlina A, Piris A, Zhang T, Halaban R, Herlyn MM, Brown KM, Wargo JA, Dummer R, Flaherty KT, Ronai ZA (2015) Downregulation of the ubiquitin ligase RNF125 underlies resistance of melanoma cells to BRAF inhibitors via JAK1 deregulation. Cell Rep 11(9):1458–1473. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Randle SJ, Laman H (2016) F-box protein interactions with the hallmark pathways in cancer. Semin Cancer Biol 36:3–17. CrossRefPubMedGoogle Scholar
  21. 21.
    Yang L, Chen J, Huang X, Zhang E, He J, Cai Z (2018) Novel insights Into E3 ubiquitin ligase in cancer chemoresistance. Am J Med Sci 355(4):368–376. CrossRefPubMedGoogle Scholar
  22. 22.
    Buetow L, Huang DT (2016) Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol 17(10):626–642. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wade M, Li Y-C, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2):83–96. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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(6):438–449. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Xu W, Taranets L, Popov N (2016) Regulating Fbw7 on the road to cancer. Semin Cancer Biol 36:62–70. CrossRefGoogle Scholar
  26. 26.
    Gossage L, Eisen T, Maher ER (2015) VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15(1):55–64. CrossRefPubMedGoogle Scholar
  27. 27.
    Li ML, Greenberg RA (2012) Links between genome integrity and BRCA1 tumor suppression. Trends Biochem Sci 37(10):418–424. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barrière C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L (2014) SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Can Res 74(20):5855–5865. CrossRefGoogle Scholar
  29. 29.
    Aguilar A, Lu J, Liu L, Du D, Bernard D, McEachern D, Przybranowski S, Li X, Luo R, Wen B, Sun D, Wang H, Wen J, Wang G, Zhai Y, Guo M, Yang D, Wang S (2017) Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): a potent and orally active murine double minute 2 (MDM2) inhibitor in clinical development. J Med Chem 60 (7):2819–2839.
  30. 30.
    So WV, Ou Yang T-H, Yang X, Zhi J (2019) Lack of UGT polymorphism association with idasanutlin pharmacokinetics in solid tumor patients. Cancer Chemother Pharmacol 83(1):209–213. CrossRefPubMedGoogle Scholar
  31. 31.
    Sluimer J, Distel B (2018) Regulating the human HECT E3 ligases. Cell Mol Life Sci 75(17):3121–3141. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zheng N, Shabek N (2017) Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem 86:129–157. CrossRefPubMedGoogle Scholar
  33. 33.
    Wenzel DM, Lissounov A, Brzovic PS, Klevit RE (2011) UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474(7349):105–108. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lorenz S (2018) Structural mechanisms of HECT-type ubiquitin ligases. Biol Chem 399(2):127–145. CrossRefPubMedGoogle Scholar
  35. 35.
    Scheffner M, Nuber U, Huibregtse JM (1995) Protein ubiquitination involving an E1–E2–E3 enzyme ubiquitin thioester cascade. Nature 373(6509):81–83CrossRefGoogle Scholar
  36. 36.
    Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP (1999) Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Science (New York, NY) 286(5443):1321–1326CrossRefGoogle Scholar
  37. 37.
    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(11):5249CrossRefGoogle Scholar
  38. 38.
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75(3):495–505CrossRefGoogle Scholar
  39. 39.
    Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y (2009) E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ 16(8):1156–1166. CrossRefPubMedGoogle Scholar
  40. 40.
    Wolyniec K, Shortt J, de Stanchina E, Levav-Cohen Y, Alsheich-Bartok O, Louria-Hayon I, Corneille V, Kumar B, Woods SJ, Opat S, Johnstone RW, Scott CL, Segal D, Pandolfi PP, Fox S, Strasser A, Jiang YH, Lowe SW, Haupt S, Haupt Y (2012) E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis. Blood 120(4):822–832. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Paul PJ, Raghu D, Chan AL, Gulati T, Lambeth L, Takano E, Herold MJ, Hagekyriakou J, Vessella RL, Fedele C, Shackleton M, Williams ED, Fox S, Williams S, Haupt S, Gamell C, Haupt Y (2016) Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP. Oncogene 35(48):6235–6245. CrossRefPubMedGoogle Scholar
  42. 42.
    Mansour M, Haupt S, Chan AL, Godde N, Rizzitelli A, Loi S, Caramia F, Deb S, Takano EA, Bishton M, Johnstone C, Monahan B, Levav-Cohen Y, Jiang YH, Yap AS, Fox S, Bernard O, Anderson R, Haupt Y (2016) The E3-ligase E6AP represses breast cancer metastasis via regulation of ECT2-Rho signaling. Can Res 76(14):4236–4248. CrossRefGoogle Scholar
  43. 43.
    Chen C, Sun X, Guo P, Dong XY, Sethi P, Zhou W, Zhou Z, Petros J, Frierson HF, Vessella RL, Atfi A, Dong JT (2007) Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Oncogene 26(16):2386–2394CrossRefGoogle Scholar
  44. 44.
    Chen C, Zhou Z, Ross JS, Zhou W, Dong JT (2007) The amplified WWP1 gene is a potential molecular target in breast cancer. Int J Cancer 121(1):80–87CrossRefGoogle Scholar
  45. 45.
    Li Y, Zhou Z, Chen C (2008) WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis. Cell Death Differ 15(12):1941–1951. CrossRefPubMedGoogle Scholar
  46. 46.
    Chen C, Sun X, Guo P, Dong XY, Sethi P, Cheng X, Zhou J, Ling J, Simons JW, Lingrel JB, Dong JT (2005) Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells. J Biol Chem 280(50):41553–41561CrossRefGoogle Scholar
  47. 47.
    Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K (2004) Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23(41):6914–6923. CrossRefPubMedGoogle Scholar
  48. 48.
    Li Y, Zhou Z, Alimandi M, Chen C (2009) WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer. Oncogene 28(33):2948–2958. CrossRefPubMedGoogle Scholar
  49. 49.
    Salah Z, Melino G, Aqeilan RI (2011) Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity. Can Res 71(5):2010–2020. CrossRefGoogle Scholar
  50. 50.
    Chang L, Shen L, Zhou H, Gao J, Pan H, Zheng L, Armstrong B, Peng Y, Peng G, Zhou BP, Rosen ST, Shen B (2019) ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response. Nucleic Acids Res 47(2):824–842.
  51. 51.
    Lin X, Liang M, Feng XH (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 275(47):36818–36822CrossRefGoogle Scholar
  52. 52.
    Tang LY, Yamashita M, Coussens NP, Tang Y, Wang XC, Li CL, Deng CX, Cheng SY, Zhang YE (2011) Ablation of Smurf2 reveals an inhibition in TGF-beta signalling through multiple mono-ubiquitination of Smad3. EMBO J 30(23):4777–4789. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Blank M, Tang Y, Yamashita M, Burkett SS, Cheng SY, Zhang YE (2012) A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. Nat Med 18(2):227–234. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X (2007) NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128(1):129–139CrossRefGoogle Scholar
  55. 55.
    Maddika S, Kavela S, Rani N, Palicharla VR, Pokorny JL, Sarkaria JN, Chen J (2011) WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol 13(6):728–733. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Yu J, Lan J, Zhu Y, Li X, Lai X, Xue Y, Jin C, Huang H (2008) The E3 ubiquitin ligase HECTD3 regulates ubiquitination and degradation of Tara. Biochem Biophys Res Commun 367(4):805–812. CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang L, Kang L, Bond W, Zhang N (2009) Interaction between syntaxin 8 and HECTd3, a HECT domain ligase. Cell Mol Neurobiol 29(1):115–121. CrossRefPubMedGoogle Scholar
  58. 58.
    Li Y, Chen X, Wang Z, Zhao D, Chen H, Chen W, Zhou Z, Zhang J, Zhang J, Li H, Chen C (2013) The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1. Neoplasia 15(1):39-IN15.
  59. 59.
    Cho JJ, Xu Z, Parthasarathy U, Drashansky TT, Helm EY, Zuniga AN, Lorentsen KJ, Mansouri S, Cho JY, Edelmann MJ, Duong DM, Gehring T, Seeholzer T, Krappmann D, Uddin MN, Califano D, Wang RL, Jin L, Li H, Lv D, Zhou D, Zhou L, Avram D (2019) Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation. Nat Commun 10(1):701. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Li Y, Kong Y, Zhou Z, Chen H, Wang Z, Hsieh YC, Zhao D, Zhi X, Huang J, Zhang J, Li H, Chen C (2013) The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8. Cell Death Dis 4:e935. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Li Y, Wu X, Li L, Liu Y, Xu C, Su D, Liu Z (2017) The E3 ligase HECTD3 promotes esophageal squamous cell carcinoma (ESCC) growth and cell survival through targeting and inhibiting caspase-9 activation. Cancer Lett 404:44–52. CrossRefPubMedGoogle Scholar
  62. 62.
    Li Z, Zhou L, Prodromou C, Savic V, Pearl LH (2017) HECTD3 mediates an HSP90-dependent degradation pathway for protein kinase clients. Cell Rep 19(12):2515–2528. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Li F, Li Y, Liang H, Xu T, Kong Y, Huang M, Xiao J, Chen X, Xia H, Wu Y, Zhou Z, Guo X, Hu C, Yang C, Cheng X, Chen C, Qi X (2018) HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection. J Clin Invest 128(9):4148–4162. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Oeckinghaus A, Wegener E, Welteke V, Ferch U, Arslan SC, Ruland J, Scheidereit C, Krappmann D (2007) Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J 26(22):4634–4645CrossRefGoogle Scholar
  65. 65.
    Kong Y, Wang Z, Huang M, Zhou Z, Li Y, Miao H, Wan X, Huang J, Mao X, Chen C (2019) CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination. Int J Cancer. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Shu T, Li Y, Wu X, Li B, Liu Z (2017) Down-regulation of HECTD3 by HER2 inhibition makes serous ovarian cancer cells sensitive to platinum treatment. Cancer Lett 411:65–73. CrossRefPubMedGoogle Scholar
  67. 67.
    Yu H, Jove R (2004) The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 4(2):97–105. CrossRefPubMedGoogle Scholar
  68. 68.
    Wu X, Li L, Li Y, Liu Z (2016) MiR-153 promotes breast cancer cell apoptosis by targeting HECTD3. Am J Cancer Res 6(7):1563–1571PubMedPubMedCentralGoogle Scholar
  69. 69.
    Liu R, Shi P, Nie Z, Liang H, Zhou Z, Chen W, Chen H, Dong C, Yang R, Liu S, Chen C (2016) Mifepristone suppresses basal triple-negative breast cancer stem cells by down-regulating KLF5 expression. Theranostics 6(4):533–544. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Liang H, Xiao J, Zhou Z, Wu J, Ge F, Li Z, Zhang H, Sun J, Li F, Liu R, Chen C (2018) Hypoxia induces miR-153 through the IRE1alpha-XBP1 pathway to fine tune the HIF1alpha/VEGFA axis in breast cancer angiogenesis. Oncogene 37(15):1961–1975. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Liang H, Ge F, Xu Y, Xiao J, Zhou Z, Liu R, Chen C (2018) miR-153 inhibits the migration and the tube formation of endothelial cells by blocking the paracrine of angiopoietin 1 in breast cancer cells. Angiogenesis 21(4):849–860. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Ekambaram P, Lee JL, Hubel NE, Hu D, Yerneni S, Campbell PG, Pollock N, Klei LR, Concel VJ, Delekta PC, Chinnaiyan AM, Tomlins SA, Rhodes DR, Priedigkeit N, Lee AV, Oesterreich S, McAllister-Lucas LM, Lucas PC (2018) The CARMA3-Bcl10-MALT1 signalosome drives NFκB activation and promotes aggressiveness in angiotensin II receptor-positive breast cancer. Can Res 78(5):1225–1240. CrossRefGoogle Scholar
  73. 73.
    Cheng L, Deng N, Yang N, Zhao X, Lin X (2019) Malt1 protease is critical in maintaining function of regulatory T cells and may be a therapeutic target for antitumor immunity. J Immunol (Baltimore, Md: 1950) 202(10):3008–3019.
  74. 74.
    Kawadler H, Gantz MA, Riley JL, Yang X (2008) The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferation. Mol Cell 31(3):415–421. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Brüstle A, Brenner D, Knobbe CB, Lang PA, Virtanen C, Hershenfield BM, Reardon C, Lacher SM, Ruland J, Ohashi PS, Mak TW (2012) The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells. J Clin Invest 122(12):4698–4709. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Paramore A, Frantz S (2003) Bortezomib. Nat Rev Drug Discov 2(8):611–612CrossRefGoogle Scholar
  77. 77.
    Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5(5):417–421. CrossRefGoogle Scholar
  78. 78.
    Qi J, Ronai ZA (2015) Dysregulation of ubiquitin ligases in cancer. Drug Resist Updat 23:1–11. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, Pramanik A, Selivanova G (2004) Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors. Nat Med 10(12):1321–1328. CrossRefPubMedGoogle Scholar
  80. 80.
    Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (New York, NY) 303(5659):844–848CrossRefGoogle Scholar
  81. 81.
    Yang Y, Ludwig RL, Jensen JP, Pierre SA, Medaglia MV, Davydov IV, Safiran YJ, Oberoi P, Kenten JH, Phillips AC, Weissman AM, Vousden KH (2005) Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7(6):547–559CrossRefGoogle Scholar
  82. 82.
    Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, Heil F, Rueger R, Graves B, Ding M, Geho D, Middleton SA, Vassilev LT, Nichols GL, Bui BN (2012) Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 13(11):1133–1140. CrossRefPubMedGoogle Scholar
  83. 83.
    Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah RB, Pienta KJ, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S (2008) Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA 105(10):3933–3938. CrossRefPubMedGoogle Scholar
  84. 84.
    Azmi AS, Aboukameel A, Banerjee S, Wang Z, Mohammad M, Wu J, Wang S, Yang D, Philip PA, Sarkar FH, Mohammad RM (2010) MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function. Eur J Cancer (Oxford, England: 1990) 46(6):1122–1131.
  85. 85.
    Zhao Y, Liu L, Sun W, Lu J, McEachern D, Li X, Yu S, Bernard D, Ochsenbein P, Ferey V, Carry JC, Deschamps JR, Sun D, Wang S (2013) Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors. J Am Chem Soc 135(19):7223–7234. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, Shargary S, Bernard D, Li X, Zhao T, Zou P, Sun D, Wang S (2013) A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J Med Chem 56(13):5553–5561. CrossRefPubMedGoogle Scholar
  87. 87.
    Lu J, McEachern D, Li S, Ellis MJ, Wang S (2016) Reactivation of p53 by MDM2 Inhibitor MI-77301 for the treatment of endocrine-resistant breast cancer. Mol Cancer Ther 15(12):2887–2893CrossRefGoogle Scholar
  88. 88.
    Nör F, Warner KA, Zhang Z, Acasigua GA, Pearson AT, Kerk SA, Helman JI, Sant’Ana Filho M, Wang S, Nör JE (2017) Therapeutic Inhibition of the MDM2-p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas. Clin Cancer Res 23(4):1036–1048. CrossRefPubMedGoogle Scholar
  89. 89.
    Andrews A, Warner K, Rodriguez-Ramirez C, Pearson AT, Nör F, Zhang Z, Kerk S, Kulkarni A, Helman JI, Brenner JC, Wicha MS, Wang S, Nör JE (2019) Ablation of cancer stem cells by therapeutic inhibition of the MDM2-p53 interaction in mucoepidermoid carcinoma. Clin Cancer Res 25(5):1588–1600. CrossRefPubMedGoogle Scholar
  90. 90.
    Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B (2013) Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 56(14):5979–5983. CrossRefPubMedGoogle Scholar
  91. 91.
    Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS (2016) System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes. Mol Cell 62(1):121–136. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Gorelik M, Orlicky S, Sartori MA, Tang X, Marcon E, Kurinov I, Greenblatt JF, Tyers M, Moffat J, Sicheri F, Sidhu SS (2016) Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1–F-box interface. Proc Natl Acad Sci 113(13):3527. CrossRefPubMedGoogle Scholar
  93. 93.
    Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W, Sidhu SS, Huang DT (2017) A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants. Mol Cell 68(2):456.e410–470.e410CrossRefGoogle Scholar
  94. 94.
    Mund T, Lewis MJ, Maslen S, Pelham HR (2014) Peptide and small molecule inhibitors of HECT-type ubiquitin ligases. Proc Natl Acad Sci USA 111(47):16736–16741. CrossRefPubMedGoogle Scholar
  95. 95.
    Rossi M, Rotblat B, Ansell K, Amelio I, Caraglia M, Misso G, Bernassola F, Cavasotto CN, Knight RA, Ciechanover A, Melino G (2014) High throughput screening for inhibitors of the HECT ubiquitin E3 ligase ITCH identifies antidepressant drugs as regulators of autophagy. Cell Death Dis 5(5):e1203. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Kathman SG, Span I, Smith AT, Xu Z, Zhan J, Rosenzweig AC, Statsyuk AV (2015) A small molecule that switches a ubiquitin ligase from a processive to a distributive enzymatic mechanism. J Am Chem Soc 137(39):12442–12445. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Sander B, Xu W, Eilers M, Popov N, Lorenz S (2017) A conformational switch regulates the ubiquitin ligase HUWE1. eLife 6.
  98. 98.
    Chen Z, Jiang H, Xu W, Li X, Dempsey DR, Zhang X, Devreotes P, Wolberger C, Amzel LM, Gabelli SB, Cole PA (2017) A tunable brake for HECT ubiquitin ligases. Mol Cell 66(3):345.e346–357.e346CrossRefGoogle Scholar
  99. 99.
    Chan AL, Grossman T, Zuckerman V, Campigli Di Giammartino D, Moshel O, Scheffner M, Monahan B, Pilling P, Jiang YH, Haupt S, Schueler-Furman O, Haupt Y (2013) c-Abl phosphorylates E6AP and regulates its E3 ubiquitin ligase activity. Biochemistry 52(18):3119–3129. CrossRefPubMedGoogle Scholar
  100. 100.
    Hamzeh-Mivehroud M, Alizadeh AA, Morris MB, Church WB, Dastmalchi S (2013) Phage display as a technology delivering on the promise of peptide drug discovery. Drug Discov Today 18(23–24):1144–1157. CrossRefPubMedGoogle Scholar
  101. 101.
    Ungermannova D, Lee J, Zhang G, Dallmann HG, McHenry CS, Liu X (2013) High-throughput screening alphascreen assay for identification of small-molecule inhibitors of ubiquitin E3 Ligase SCFSkp2-Cks1. J Biomol Screen 18(8):910–920. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H (2016) Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 15(9):605–619. CrossRefPubMedGoogle Scholar
  103. 103.
    Gu L, Zhang H, Liu T, Zhou S, Du Y, Xiong J, Yi S, Qu CK, Fu H, Zhou M (2016) Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell 30(4):623–636CrossRefGoogle Scholar
  104. 104.
    Krist DT, Park S, Boneh GH, Rice SE, Statsyuk AV (2016) UbFluor: a mechanism-based probe for HECT E3 ligases. Chem Sci 7(8):5587–5595. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Veggiani G, Gerpe MCR, Sidhu SS, Zhang W (2019) Emerging drug development technologies targeting ubiquitination for cancer therapeutics. Pharmacol TherGoogle Scholar
  106. 106.
    Franzini RM, Neri D, Scheuermann J (2014) DNA-encoded chemical libraries: advancing beyond conventional small-molecule libraries. Acc Chem Res 47(4):1247–1255. CrossRefPubMedGoogle Scholar
  107. 107.
    Rognan D (2017) The impact of in silico screening in the discovery of novel and safer drug candidates. Pharmacol Ther 175:47–66CrossRefGoogle Scholar
  108. 108.
    Li Y, Xie P, Lu L, Wang J, Diao L, Liu Z, Guo F, He Y, Liu Y, Huang Q, Liang H, Li D, He F (2017) An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network. Nat Commun 8(1):347. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Herman AG, Hayano M, Poyurovsky MV, Shimada K, Skouta R, Prives C, Stockwell BR (2011) Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay. Cancer Discov 1(4):312–325. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Tian M, Zeng T, Liu M, Han S, Lin H, Lin Q, Li L, Jiang T, Li G, Lin H, Zhang T, Kang Q, Deng X, Wang H-R (2019) A cell-based high-throughput screening method based on a ubiquitin-reference technique for identifying modulators of E3 ligases. J Biol Chem 294(8):2880–2891. CrossRefPubMedGoogle Scholar
  111. 111.
    Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S (2013) Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res 12(1):260–271. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Qiuyun Jiang
    • 1
    • 2
  • Fubing Li
    • 3
  • Zhuo Cheng
    • 1
    • 2
  • Yanjie Kong
    • 4
  • Ceshi Chen
    • 1
    • 2
    • 5
    Email author
  1. 1.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingChina
  2. 2.Kunming College of Life ScienceUniversity of the Chinese Academy of SciencesKunmingChina
  3. 3.Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhouChina
  4. 4.Institute of Translation Medicine, Shenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhenChina
  5. 5.KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingChina

Personalised recommendations