Skip to main content

The role of E3 ubiquitin ligase HECTD3 in cancer and beyond

Cellular and Molecular Life Sciences volume 77, pages 1483–1495 (2020)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

ACC:

Adrenocortical carcinoma

ANGPT1:

Angiopoietin 1

BRCA:

Breast invasive carcinoma

BRCA1:

Breast cancer type 1 susceptibility protein

c-Abl:

Abelson murine leukemia viral homolog 1

CHOL:

Cholangiocarcinoma

CRAF:

RAF proto-oncogene serine/threonine-protein kinase

CRL7:

Cullin-RING E3 ubiquitin ligase 7

CUL1:

Cullin1

CUL7:

Cullin 7

DECL:

DNA-encoded compound libraries

DISC:

Death-inducing signaling complex

DLBC:

Lymphoid neoplasm diffuse large B-cell lymphoma

DUB:

Deubiquitinating enzyme

E1:

Ubiquitin-activating enzyme

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin ligase

E6-AP:

E6-associated protein

EAE:

Experimental autoimmune encephalomyelitis

ECT2:

Epithelial cell transforming 2

EGFR:

Epidermal growth factor receptor

ER:

Endoplasmic reticulum

ERBB4:

Erb-b2 receptor tyrosine kinase 4

ERK:

Mitogen-activated protein kinase 1

ESCC:

Esophageal squamous cell carcinoma

FBDD:

Fragment-based drug discovery

FBW7:

F-box and WD repeat domain containing 7

FP-HTS:

Fluorescence polarization assay for high-throughput screening

HECT:

Homologous to E6AP C terminus

HECTD3:

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

HER2:

Erb-b2 receptor tyrosine kinase 2

HIF1α:

Hypoxia inducible factor 1 subunit alpha

HSP90:

Heat shock protein 90

HTS:

High-throughput screening technologies

HUWE1:

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

IFN:

Interferon

IRE1α:

Inositol requiring enzyme 1 alpha

IRF3:

Interferon regulatory factor 3

ITCH:

Itchy E3 ubiquitin protein ligase

KLF5:

Kruppel like factor 5

LATS1:

Large tumor suppressor kinase 1

LIHC:

Liver hepatocellular carcinoma

LGG:

Brain lower grade glioma

LUAD:

Lung adenocarcinoma

MALT1:

MALT1 paracaspase

MCL1:

Myeloid cell leukemia 1

MDM2:

Murine double minute 2

miR-153:

MicroRNA-153

NEDD4-1:

NEDD4 E3 ubiquitin protein ligase

OV:

Ovarian serous cystadenocarcinoma

PMA:

Phorbol-12-myristate-13-acetate

PML:

Promyelocytic leukemia protein

PTEN:

Phosphatase and tensin homolog

RBR:

RING-IBR-RINGs

RING:

Really interesting new genes

RLD:

RCC1 like domain

RNF20:

Ring finger protein 20

RORγt:

Retineic-acid-receptor-related orphan nuclear receptor γ

SCF:

SKP1-CUL1-F-box protein

SKP2:

S-phase kinase-associated protein 2

SMAD2:

SMAD family member 2

SMURF2:

SMAD specific E3 ubiquitin protein ligase 2

Stat3:

Signal transducer and activator of transcription 3

Tara:

Trio-associated repeat on actin

TBK1:

TANK binding kinase 1

TGFβ:

Transforming growth factor β

TGFβR1:

Transforming growth factor β receptor 1

Th17:

T helper 17

THCA:

Thyroid carcinoma

THYM:

Thymoma

TNBC:

Triple negative breast cancer

TRAF3:

TNF receptor-associated factor 3

TRAF6:

TNF receptor-associated factor 6

TRAIL:

TNF-related apoptosis-inducing ligand

Ub:

Ubiquitin

UCEC:

Uterine Corpus Endometrial Carcinoma

UCS:

Uterine Carcinosarcoma

UbV:

Ub variant

UCS:

Uterine carcinosarcoma

VCB-CR:

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

VHL:

Von Hippel–Lindau disease tumor suppressor

WWP1:

WW domain containing E3 ubiquitin protein ligase 1

WWP2:

WW domain containing E3 ubiquitin protein ligase 2

XBP1:

X-box binding protein 1

References

  1. Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503–533

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229. https://doi.org/10.1146/annurev-biochem-060310-170328

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1038/ncb1821. https://www.nature.com/articles/ncb1821#supplementary-information

  5. Trempe JF (2011) Reading the ubiquitin postal code. Curr Opin Struct Biol 21(6):792–801. https://doi.org/10.1016/j.sbi.2011.09.009

    Article  PubMed  CAS  Google Scholar 

  6. Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10(6):398–409. https://doi.org/10.1038/nrm2690

    Article  PubMed  CAS  Google Scholar 

  7. Haglund K, Dikic I (2005) Ubiquitylation and cell signaling. EMBO J 24(19):3353–3359. https://doi.org/10.1038/sj.emboj.7600808

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Hoeller D, Hecker CM, Dikic I (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 6(10):776–788. https://doi.org/10.1038/nrc1994

    Article  PubMed  CAS  Google Scholar 

  9. Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science (New York, NY) 315(5809):201–205. https://doi.org/10.1126/science.1127085

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/nrm2831

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1038/nrm3143

    Article  PubMed  CAS  Google Scholar 

  12. Gilberto S, Peter M (2017) Dynamic ubiquitin signaling in cell cycle regulation. J Cell Biol 216(8):2259–2271. https://doi.org/10.1083/jcb.201703170

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Senft D, Qi J, Ronai ZA (2018) Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18(2):69–88. https://doi.org/10.1038/nrc.2017.105

    Article  PubMed  CAS  Google Scholar 

  14. Popovic D, Vucic D, Dikic I (2014) Ubiquitination in disease pathogenesis and treatment. Nat Med 20(11):1242–1253. https://doi.org/10.1038/nm.3739

    Article  PubMed  CAS  Google Scholar 

  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 177:96–107

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/nrd.2017.152

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2012.02.065

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Dubrez L, Rajalingam K (2015) IAPs and cell migration. Semin Cell Dev Biol 39:124–131. https://doi.org/10.1016/j.semcdb.2015.02.015

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.celrep.2015.04.049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Randle SJ, Laman H (2016) F-box protein interactions with the hallmark pathways in cancer. Semin Cancer Biol 36:3–17. https://doi.org/10.1016/j.semcancer.2015.09.013

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.amjms.2017.12.012

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrm.2016.91

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/nrc3430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/nrc2396

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Xu W, Taranets L, Popov N (2016) Regulating Fbw7 on the road to cancer. Semin Cancer Biol 36:62–70. https://doi.org/10.1016/j.semcancer.2015.09.005

    Article  PubMed  CAS  Google Scholar 

  26. Gossage L, Eisen T, Maher ER (2015) VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15(1):55–64. https://doi.org/10.1038/nrc3844

    Article  PubMed  CAS  Google Scholar 

  27. Li ML, Greenberg RA (2012) Links between genome integrity and BRCA1 tumor suppression. Trends Biochem Sci 37(10):418–424. https://doi.org/10.1016/j.tibs.2012.06.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.Can-14-0799

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1021/acs.jmedchem.6b01665

  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. https://doi.org/10.1007/s00280-018-3741-2

    Article  PubMed  CAS  Google Scholar 

  31. Sluimer J, Distel B (2018) Regulating the human HECT E3 ligases. Cell Mol Life Sci 75(17):3121–3141. https://doi.org/10.1007/s00018-018-2848-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Zheng N, Shabek N (2017) Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem 86:129–157. https://doi.org/10.1146/annurev-biochem-060815-014922

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1038/nature09966

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Lorenz S (2018) Structural mechanisms of HECT-type ubiquitin ligases. Biol Chem 399(2):127–145. https://doi.org/10.1515/hsz-2017-0184

    Article  PubMed  CAS  Google Scholar 

  35. Scheffner M, Nuber U, Huibregtse JM (1995) Protein ubiquitination involving an E1–E2–E3 enzyme ubiquitin thioester cascade. Nature 373(6509):81–83

    Article  CAS  Google Scholar 

  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):1321–1326

    Article  CAS  Google Scholar 

  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):5249

    Article  CAS  Google Scholar 

  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):495–505

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/cdd.2009.31

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1182/blood-2011-10-387647

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/onc.2016.159

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.Can-15-1553

    Article  CAS  Google Scholar 

  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):2386–2394

    Article  CAS  Google Scholar 

  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):80–87

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/cdd.2008.134

    Article  PubMed  CAS  Google Scholar 

  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):41553–41561

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/sj.onc.1207885

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1038/onc.2009.162

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.Can-10-3516

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1093/nar/gky1199

  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):36818–36822

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/emboj.2011.393

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/nm.2596

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):129–139

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/ncb2240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.bbrc.2008.01.022

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1007/s10571-008-9303-0

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1593/neo.121362

  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. https://doi.org/10.1038/s41467-019-08605-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/cddis.2013.464

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.canlet.2017.07.004

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.celrep.2017.05.078

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1172/JCI120406

    Article  PubMed  PubMed Central  Google Scholar 

  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):4634–4645

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1002/ijc.32239

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.canlet.2017.09.048

    Article  PubMed  CAS  Google Scholar 

  67. Yu H, Jove R (2004) The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 4(2):97–105. https://doi.org/10.1038/nrc1275

    Article  PubMed  CAS  Google Scholar 

  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):1563–1571

    PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.7150/thno.14315

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/s41388-017-0089-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1007/s10456-018-9630-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.Can-17-1089

    Article  CAS  Google Scholar 

  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. https://doi.org/10.4049/jimmunol.1801614

  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. https://doi.org/10.1016/j.molcel.2008.06.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1172/jci63528

    Article  PubMed  PubMed Central  Google Scholar 

  76. Paramore A, Frantz S (2003) Bortezomib. Nat Rev Drug Discov 2(8):611–612

    Article  CAS  Google Scholar 

  77. Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5(5):417–421. https://doi.org/10.1016/S1535-6108(04)00120-5

    Article  PubMed  CAS  Google Scholar 

  78. Qi J, Ronai ZA (2015) Dysregulation of ubiquitin ligases in cancer. Drug Resist Updat 23:1–11. https://doi.org/10.1016/j.drup.2015.09.001

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nm1146

    Article  PubMed  CAS  Google Scholar 

  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):844–848

    Article  CAS  Google Scholar 

  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):547–559

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/s1470-2045(12)70474-6

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.0708917105

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ejca.2010.01.015

  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. https://doi.org/10.1021/ja3125417

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1021/jm4005708

    Article  PubMed  CAS  Google Scholar 

  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):2887–2893

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.Ccr-16-1235

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.Ccr-17-2730

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1021/jm400487c

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.molcel.2016.02.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.1519389113

    Article  PubMed  CAS  Google Scholar 

  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.e410

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.1412152111

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1038/cddis.2014.113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1021/jacs.5b06839

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Sander B, Xu W, Eilers M, Popov N, Lorenz S (2017) A conformational switch regulates the ubiquitin ligase HUWE1. eLife 6. https://doi.org/10.7554/elife.21036

  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.e346

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1021/bi301710c

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.drudis.2013.09.001

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1177/1087057113485789

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1038/nrd.2016.109

    Article  PubMed  CAS  Google Scholar 

  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):623–636

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1039/C6SC01167E

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Veggiani G, Gerpe MCR, Sidhu SS, Zhang W (2019) Emerging drug development technologies targeting ubiquitination for cancer therapeutics. Pharmacol Ther

  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. https://doi.org/10.1021/ar400284t

    Article  PubMed  CAS  Google Scholar 

  107. Rognan D (2017) The impact of in silico screening in the discovery of novel and safer drug candidates. Pharmacol Ther 175:47–66

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/s41467-017-00299-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1158/2159-8290.Cd-11-0104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.ra118.003822

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1021/pr300630k

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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).

Author information

Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Qiuyun Jiang, Zhuo Cheng & Ceshi Chen

  2. Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650204, China

    Qiuyun Jiang, Zhuo Cheng & Ceshi Chen

  3. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China

    Fubing Li

  4. Institute of Translation Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China

    Yanjie Kong

  5. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Ceshi Chen

Authors
  1. Qiuyun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fubing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhuo Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanjie Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ceshi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ceshi Chen.

Ethics declarations

Conflict of interest

The authors have no conflict of interest.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jiang, Q., Li, F., Cheng, Z. et al. The role of E3 ubiquitin ligase HECTD3 in cancer and beyond. Cell. Mol. Life Sci. 77, 1483–1495 (2020). https://doi.org/10.1007/s00018-019-03339-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-019-03339-3

Keywords

  • Ubiquitination
  • HECTD3
  • Cancer
  • Inhibitors