Targeting Protein Degradation in Cancer Treatment

Imane      Bjij; Ismail       Hdoufane; Mahmoud       Soliman; Menče       Najdoska-Bogdanov; Driss       Cherqaoui
doi:10.2174/2212796814999200609131623
Abstract

The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein, we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.
Keywords: Ubiquitin proteasome system, protein, cancer treatment, tumor suppressor genes, oncogenes, tumorgenesis.
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[1] 
Zhu K, Liu Q, Zhou Y, et al. Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. BMC Genomics  2015; 16(Suppl. 7): S8.
[http://dx.doi.org/10.1186/1471-2164-16-S7-S8] [PMID: 26099335] 
[2] 
Balaburski GM, Budina A, Murphy ME. Oncogenes and tumor suppressor genes in autophagy.  Autophagy and Cancer 2013; pp. 127-43.
[http://dx.doi.org/10.1007/978-1-4614-6561-4_7] 
[3] 
Armstrong SR, Wu H, Wang B, et al. he regulation of tumor suppressor p63 by the ubiquitin-proteasome system International Journal of Molecular Sciences 17. 
[http://dx.doi.org/10.3390/ijms17122041] 
[4] 
Burger AM, Seth AK. The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer  2004; 40(15): 2217-29.
[http://dx.doi.org/10.1016/j.ejca.2004.07.006] [PMID: 15454246] 
[5] 
Jeong WJ, Park JC, Kim WS, et al. WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation Nat Commun 10. 
[http://dx.doi.org/10.1038/s41467-018-08230-6] 
[6] 
Al-Banna L, Sadder MT, Lafi HA, Dawabah AAM, Al-Nadhari SN. Bioinformatics analysis of ubiquitin expression protein gene from Heterodera latipons. Saudi J Biol Sci  2019; 26(7): 1463-7.
[http://dx.doi.org/10.1016/j.sjbs.2018.06.005] [PMID: 31762610] 
[7] 
Callis J. The ubiquitination machinery of the ubiquitin systemArabidopsis Book  2014.12e0174. 
[http://dx.doi.org/10.1199/tab.0174] [PMID: 25320573] 
[8] 
Morreale FE, Walden H. Types of Ubiquitin Ligases. Cell  2016; 165(1): 248-248.e1.
[http://dx.doi.org/10.1016/j.cell.2016.03.003] [PMID: 27015313] 
[9] 
Van Dyken SJ, Locksley RM. Interleukin-4- and Interleukin-13-mediated alternatively activated macrophages: Roles in homeostasis and disease. Annu Rev Immunol  2013; 31: 317-43.
[http://dx.doi.org/10.1146/annurev-immunol-032712-095906] 
[10] 
Hyer ML, Milhollen MA, Ciavarri J, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med  2018; 24(2): 186-93.
[http://dx.doi.org/10.1038/nm.4474] [PMID: 29334375] 
[11] 
Akpinar HA, Kahraman H, Yaman I. Ochratoxin a sequentially activates autophagy and the ubiquitinproteasome system Toxins (Basel) 11 
[http://dx.doi.org/10.3390/toxins11110615] 
[12] 
Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol  2017; 14(7): 417-33.
[http://dx.doi.org/10.1038/nrclinonc.2016.206] [PMID: 28117417] 
[13] 
Devoy A, Soane T, Welchman R, Mayer RJ. The ubiquitin-proteasome system and cancer. Essays Biochem  2005; 41: 187-203.
[http://dx.doi.org/10.1042/EB0410187] [PMID: 16250906] 
[14] 
Diehl JA, Fuchs SY, Haines DS. Ubiquitin and cancer: new discussions for a new journal. Genes Cancer  2010; 1(7): 679-80.
[http://dx.doi.org/10.1177/1947601910383565] [PMID: 21779465] 
[15] 
Soave CL, Guerin T, Liu J, Dou QP. Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing. Cancer Metastasis Rev  2017; 36(4): 717-36.
[http://dx.doi.org/10.1007/s10555-017-9705-x] [PMID: 29047025] 
[16] 
Zhang Y, Loh C, Chen J, Mainolfi N. Targeted protein degradation mechanisms. Drug Discov Today Technol  2019; 31: 53-60.
[http://dx.doi.org/10.1016/j.ddtec.2019.01.001] [PMID: 31200860] 
[17] 
Mainolfi N, Rasmusson T. Targeted Protein DegradationAnnual Reports in Medicinal Chemistry.  Academic Press Inc. 2017; pp. 301-34.
[18] 
Chen D, Wan SB, Yang H, et al. EGCG, green tea polyphenols and their synthetic analogs and prodrugs for human cancer prevention and treatment 2011.
[http://dx.doi.org/10.1016/B978-0-12-385855-9.00007-2] 
[19] 
Wustrow D, Zhou HJ, Rolfe M. Inhibition of ubiquitin proteasome system enzymes for anticancer therapy. Annu Rep Med Chem  2013; 48: 205-25.
[http://dx.doi.org/10.1016/B978-0-12-417150-3.00014-4] 
[20] 
Pasqua AE, Wilding B, Cheeseman MD, et al. Targeting protein synthesis, folding, and degradation pathways in cancerComprehensive medicinal chemistry III.  US: Elsevier Inc. 2017; pp. 202-80.
[http://dx.doi.org/10.1016/B978-0-12-409547-2.12395-9] 
[21] 
Castaldi MP, Zuhl A, Ricchiuto P, et al. Chemical Biology in Drug DiscoveryAnnual Reports in Medicinal Chemistry.  Academic Press Inc. 2017; pp. 335-70.
[22] 
Plettenburg O. The Impact of Chemical Biology on Drug Discovery. Isr J Chem  2019; 59: 29-36.
[http://dx.doi.org/10.1002/ijch.201900007] 
[23] 
Korhonen L, Putkonen N, Lindholm D. Proteasome Role in NeurodegenerationEncyclopedia of Neuroscience.  Elsevier Ltd 2009; pp. 1157-62.
[http://dx.doi.org/10.1016/B978-008045046-9.00535-0] 
[24] 
Lindholm D, Hyrskyluoto A, Bruelle C, et al. Proteasome role in neurodegenerationReference Module in biomedical sciences. US: Elsevier 2015.
[http://dx.doi.org/10.1016/B978-0-12-801238-3.04736-X] 
[25] 
Narayanan S, Cai CY, Assaraf YG, et al.  Targeting the ubiquitin-proteasome pathway to overcome anticancer drug resistance Drug Resist Updat 48. 
[http://dx.doi.org/10.1016/j.drup.2019.100663] 
[26] 
Schwartz AL, Ciechanover A. The ubiquitin-proteasome pathway and pathogenesis of human diseases. Annu Rev Med  1999; 50: 57-74.
[http://dx.doi.org/10.1146/annurev.med.50.1.57] 
[27] 
Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem  1998; 67: 425-79.
[http://dx.doi.org/10.1146/annurev.biochem.67.1.425] [PMID: 9759494] 
[28] 
Díaz-Villanueva JF, Díaz-Molina R, García-González V. Protein folding and mechanisms of proteostasis. Int J Mol Sci  2015; 16(8): 17193-230.
[http://dx.doi.org/10.3390/ijms160817193] [PMID: 26225966] 
[29] 
Heinemeyer WPC, Ramos RD. Ubiquitin-proteasome system. Cell Mol Life Sci  2004; 61: 1562-78.
[http://dx.doi.org/10.1007/s00018-004-4130-z] [PMID: 15224181] 
[30] 
Gallastegui N, Groll M. The 26S proteasome: assembly and function of a destructive machine. Trends Biochem Sci  2010; 35(11): 634-42.
[http://dx.doi.org/10.1016/j.tibs.2010.05.005] [PMID: 20541423] 
[31] 
Stadtmueller BM, Kish-Trier E, Ferrell K, et al. Structure of a proteasome Pba1-Pba2 complex: implications for proteasome assembly, activation, and biological function. J Biol Chem  2012; 287(44): 37371-82.
[http://dx.doi.org/10.1074/jbc.M112.367003] [PMID: 22930756] 
[32] 
Murata S, Yashiroda H, Tanaka K. Molecular mechanisms of proteasome assembly. Nat Rev Mol Cell Biol  2009; 10(2): 104-15.
[http://dx.doi.org/10.1038/nrm2630] [PMID: 19165213] 
[33] 
Hendil KB, Hartmann-Petersen R, Tanaka K. 26 S proteasomes function as stable entities. J Mol Biol  2002; 315(4): 627-36.
[http://dx.doi.org/10.1006/jmbi.2001.5285] [PMID: 11812135] 
[34] 
Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem  1999; 68: 1015-68.
[http://dx.doi.org/10.1146/annurev.biochem.68.1.1015] [PMID: 10872471] 
[35] 
Bedford L, Paine S, Sheppard PW, Mayer RJ, Roelofs J. Assembly, structure, and function of the 26S proteasome. Trends Cell Biol  2010; 20(7): 391-401.
[http://dx.doi.org/10.1016/j.tcb.2010.03.007] [PMID: 20427185] 
[36] 
Asano S, Fukuda Y, Beck F, et al. A molecular census of 26S proteasomes in intact neurons Science (80) 2015.347: 439-42.. 
[37] 
Tohe A. Structure and function of the yeast 26S proteasome. Seikagaku  1999; 71(3): 173-81.
[PMID: 10332219] 
[38] 
Tomko RJ Jr, Hochstrasser M. Molecular architecture and assembly of the eukaryotic proteasome. Annu Rev Biochem  2013; 82: 415-45.
[http://dx.doi.org/10.1146/annurev-biochem-060410-150257] [PMID: 23495936] 
[39] 
Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem  1996; 65: 801-47.
[http://dx.doi.org/10.1146/annurev.bi.65.070196.004101] [PMID: 8811196] 
[40] 
Collins GA, Goldberg AL. The Logic of the 26S proteasome. Cell  2017; 169(5): 792-806.
[http://dx.doi.org/10.1016/j.cell.2017.04.023] [PMID: 28525752] 
[41] 
Aufderheide A, Beck F, Stengel F, et al. Structural characterization of the interaction of Ubp6 with the 26S proteasome. Proc Natl Acad Sci USA  2015; 112(28): 8626-31.
[http://dx.doi.org/10.1073/pnas.1510449112] [PMID: 26130806] 
[42] 
Livneh I, Cohen-Kaplan V, Cohen-Rosenzweig C, Avni N, Ciechanover A. The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res  2016; 26(8): 869-85.
[http://dx.doi.org/10.1038/cr.2016.86] [PMID: 27444871] 
[43] 
Morozov AV, Burov AV, Astakhova TM, Spasskaya DS, Margulis BA, Karpov VL. Dynamics of the functional activity and expression of proteasome subunits during cellular adaptation to heat shock Mol Biol (Mosk)  2019; 53(4): 638-47.
[PMID: 31397437] 
[44] 
Pickart CM, Cohen RE. Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Biol  2004; 5(3): 177-87.
[http://dx.doi.org/10.1038/nrm1336] [PMID: 14990998] 
[45] 
Bhogaraju S, Dikic I. Cell biology: Ubiquitination without E1 and E2 enzymes. Nature  2016; 533(7601): 43-4.
[http://dx.doi.org/10.1038/nature17888] [PMID: 27096359] 
[46] 
Verhamme IM, Leonard SE, Perkins RC. Proteases: Pivot points in functional proteomics.In: Walker JM, Ed. Methods in molecular biology.  US: Humana Press Inc. 2019; pp. 313-92.
[47] 
Fan J, Ning B, Lyon CJ, et al. Circulating peptidome and tumor-resident proteolysis. In: Tamanoi F, Ed.Enzymes.  US: Academic Press 2017; pp. 1-25.
[http://dx.doi.org/10.1016/bs.enz.2017.08.001] 
[48] 
Zaveri NT, Murphy BJ. Nuclear hormone receptors
Comprehensive Medicinal Chemistry II Elsevier.  2006.993-1036. 
[49] 
Platta HW, Thoms S, Kunau WH, et al. Function of the Ubiquitin-Conjugating Enzyme Pex4p and the AAA Peroxin Complex Pex1p/Pex6p in Peroxisomal Matrix Protein TransportEnzymes.  Academic Press 2007; pp. 541-72.
[50] 
Weake VM, Workman JL. Histone ubiquitinationHandbook of Cell Signaling, 2/e.  Elsevier Inc. 2010; pp. 2449-60.
[http://dx.doi.org/10.1016/B978-0-12-374145-5.00292-8] 
[51] 
Verma S, Shukla S, Pandey M, et al. Differentially expressed genes and molecular pathways in an autochthonous mouse prostate cancer model. Front Genet  2019; 10: 235.
[http://dx.doi.org/10.3389/fgene.2019.00235] 
[52] 
Seo J, Kim MW, Bae KH, Lee SC, Song J, Lee EW. The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics. Biochem Pharmacol  2019; 162: 21-40.
[http://dx.doi.org/10.1016/j.bcp.2018.11.012] [PMID: 30452908] 
[53] 
Gómez-Díaz C, Ikeda F. Roles of ubiquitin in autophagy and cell death. Semin Cell Dev Biol  2019; 93: 125-35.
[http://dx.doi.org/10.1016/j.semcdb.2018.09.004] [PMID: 30195063] 
[54] 
Asaoka T, Ikeda F. New Insights into the Role of Ubiquitin Networks in the Regulation of Antiapoptosis Pathways. Int Rev Cell Mol Biol  2015; 318: 121-58.
[http://dx.doi.org/10.1016/bs.ircmb.2015.05.003] [PMID: 26315885] 
[55] 
Lendahl U. Cell biology at high resolution. Exp Cell Res  2015; 337: v.
[http://dx.doi.org/10.1016/S0014-4827(15)00260-8] 
[56] 
Tan WH, Gilmore EC, Baris HN. Human developmental
genetics. In: Rimoin D, Pyeritz R, Korf B,
Eds. Emery and Rimoin’s principles and practice of
medical genetics. US: Elsevier Ltd.  2013; pp. 1-63.
[http://dx.doi.org/10.1016/B978-0-12-383834-6.00018-5] 
[57] 
Pyeritz RE. Pathogenetics of disease. In: Rimoin D,
Pyeritz R, Korf B, Eds. Emery and Rimoin’s principles
and practice of medical genetics. US: Elsevier
Ltd  2013; pp. 1-13 . 
[58] 
Yang Y, Kitagaki J, Dai RM, et al. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res  2007; 67(19): 9472-81.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0568] [PMID: 17909057] 
[59] 
Xu GW, Ali M, Wood TE, et al. The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood  2010; 115(11): 2251-9.
[http://dx.doi.org/10.1182/blood-2009-07-231191] [PMID: 20075161] 
[60] 
Okamoto Y, Ozaki T, Miyazaki K, Aoyama M, Miyazaki M, Nakagawara A. UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme. Cancer Res  2003; 63(14): 4167-73.
[PMID: 12874022] 
[61] 
van Wijk SJ, Timmers HTM. The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins. FASEB J  2010; 24(4): 981-93.
[http://dx.doi.org/10.1096/fj.09-136259] [PMID: 19940261] 
[62] 
Hosseini SM, Okoye I, Chaleshtari MG, et al. E2 ubiquitin-conjugating enzymes in cancer: Implications for immunotherapeutic interventions. Clin Chim Acta  2019; 498: 126-34.
[http://dx.doi.org/10.1016/j.cca.2019.08.020] [PMID: 31445029] 
[63] 
David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin-conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem  2010; 285(12): 8595-604.
[http://dx.doi.org/10.1074/jbc.M109.089003] [PMID: 20061386] 
[64] 
Pulvino M, Liang Y, Oleksyn D, et al. Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A. Blood  2012; 120(8): 1668-77.
[http://dx.doi.org/10.1182/blood-2012-02-406074] [PMID: 22791293] 
[65] 
Strickson S, Campbell DG, Emmerich CH, et al. The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system. Biochem J  2013; 451(3): 427-37.
[http://dx.doi.org/10.1042/BJ20121651] [PMID: 23441730] 
[66] 
Sanders MA, Brahemi G, Nangia-Makker P, et al. Novel inhibitors of Rad6 ubiquitin conjugating enzyme: design, synthesis, identification, and functional characterization. Mol Cancer Ther  2013; 12(4): 373-83.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0793] [PMID: 23339190] 
[67] 
Valimberti I, Tiberti M, Lambrughi M, et al. E2 superfamily of ubiquitin-conjugating enzymes: constitutively active or activated through phosphorylation in the catalytic cleft. Sci Rep  2015; 5: 14849.
[http://dx.doi.org/10.1038/srep14849] 
[68] 
Payne S. Immunity and resistance to viruses. In: Payne S, Ed Viruses.  US: Elsevier 2017; pp. 61-71.
[http://dx.doi.org/10.1016/B978-0-12-803109-4.00006-4] 
[69] 
Murr R.  2010.Interplay between different epigenetic modifications and mechanisms.In: Kumar D, Ed. Advances in genetics 2010.70: 101-41.. 
[http://dx.doi.org/10.1016/B978-0-12-380866-0.60005-8] 
[70] 
Hegde AN. Ubiquitin-proteasome system and plasticity.In: Squire LR, Ed.Encyclopedia of neuroscience.  Elsevier Ltd 2009; pp. 1-9.
[http://dx.doi.org/10.1016/B978-008045046-9.00827-5] 
[71] 
Hegde AN. Proteolysis and synaptic plasticity.In:Byrne JH, Ed.Learning and memory: A comprehensive reference.  US: Elsevier 2007; pp. 525-45.
[72] 
Edwin F, Anderson K, Patel TB. HECT domain-containing E3 ubiquitin ligase Nedd4 interacts with and ubiquitinates Sprouty2. J Biol Chem  2010; 285(1): 255-64.
[http://dx.doi.org/10.1074/jbc.M109.030882] [PMID: 19864419] 
[73] 
Sugeno N, Hasegawa T, Tanaka N, et al. Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitates endosomal sequestration of internalized α-synuclein. J Biol Chem  2014; 289(26): 18137-51.
[http://dx.doi.org/10.1074/jbc.M113.529461] [PMID: 24831002] 
[74] 
Vander Kooi CW, Ohi MD, Rosenberg JA, et al. The Prp19 U-box crystal structure suggests a common dimeric architecture for a class of oligomeric E3 ubiquitin ligases. Biochemistry  2006; 45(1): 121-30.
[http://dx.doi.org/10.1021/bi051787e] [PMID: 16388587] 
[75] 
Zou X, Levy-Cohen G, Blank M. Molecular functions of NEDD4 E3 ubiquitin ligases in cancer. Biochim Biophys Acta  2015; 1856(1): 91-106.
[PMID: 26116757] 
[76] 
Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene  2004; 23(11): 1972-84.
[http://dx.doi.org/10.1038/sj.onc.1207436] [PMID: 15021885] 
[77] 
Sun Y. E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia  2006; 8(8): 645-54.
[http://dx.doi.org/10.1593/neo.06376] [PMID: 16925947] 
[78] 
Bjij I, Khan S, Betz R, Cherqaoui D, Soliman MES. Exploring the structural mechanism of covalently bound e3 ubiquitin ligase: catalytic or allosteric inhibition? Protein J  2018; 37(6): 500-9.
[http://dx.doi.org/10.1007/s10930-018-9795-5] [PMID: 30232697] 
[79] 
Zhu K, Shan Z, Chen X, et al. Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch. EMBO Rep  2017; 18(9): 1618-30.
[http://dx.doi.org/10.15252/embr.201744454] [PMID: 28747490] 
[80] 
Ong JY, Torres JZ. E3 Ubiquitin ligases in cancer and their pharmacological targeting.In: Summers M, Ed.Ubiquitin proteasome system - current insights into mechanism cellular regulation and disease. UK: IntechOpen 2019.
[http://dx.doi.org/10.5772/intechopen.82883] 
[81] 
Zheng N, Shabek N. Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem  2017; 86: 129-57.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014922] [PMID: 28375744] 
[82] 
Kerscher O, Felberbaum R, Hochstrasser M. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol  2006; 22: 159-80.
[http://dx.doi.org/10.1146/annurev.cellbio.22.010605.093503] [PMID: 16753028] 
[83] 
Berndsen CE, Wolberger C. New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol  2014; 21(4): 301-7.
[http://dx.doi.org/10.1038/nsmb.2780] [PMID: 24699078] 
[84] 
Ulrich HD, Walden H. Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol  2010; 11(7): 479-89.
[http://dx.doi.org/10.1038/nrm2921] [PMID: 20551964] 
[85] 
Liu L, Wong CC, Gong B, Yu J. Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer. Oncogene  2018; 37(2): 148-59.
[http://dx.doi.org/10.1038/onc.2017.313] [PMID: 28925398] 
[86] 
Liew CW, Sun H, Hunter T, Day CL. RING domain dimerization is essential for RNF4 function. Biochem J  2010; 431(1): 23-9.
[http://dx.doi.org/10.1042/BJ20100957] [PMID: 20681948] 
[87] 
Leslie PL, Ke H, Zhang Y. The MDM2 RING domain and central acidic domain play distinct roles in MDM2 protein homodimerization and MDM2-MDMX protein heterodimerization. J Biol Chem  2015; 290(20): 12941-50.
[http://dx.doi.org/10.1074/jbc.M115.644435] [PMID: 25809483] 
[88] 
Calabrese MF, Scott DC, Duda DM, et al. A RING E3-substrate complex poised for ubiquitin-like protein transfer: structural insights into cullin-RING ligases. Nat Struct Mol Biol  2011; 18(8): 947-9.
[http://dx.doi.org/10.1038/nsmb.2086] [PMID: 21765416] 
[89] 
Deshaies RJ, Joazeiro CAP. RING domain E3 ubiquitin ligases. Annu Rev Biochem  2009; 78: 399-434.
[http://dx.doi.org/10.1146/annurev.biochem.78.101807.093809] [PMID: 19489725] 
[90] 
Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta  2014; 1843(1): 47-60.
[http://dx.doi.org/10.1016/j.bbamcr.2013.05.026] [PMID: 23747565] 
[91] 
Komander D, Rape M. The ubiquitin code. Annu Rev Biochem  2012; 81: 203-29.
[http://dx.doi.org/10.1146/annurev-biochem-060310-170328] [PMID: 22524316] 
[92] 
Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem  2005; 41: 15-30.
[http://dx.doi.org/10.1042/EB0410015] [PMID: 16250895] 
[93] 
Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans  2009; 37(Pt 5): 937-53.
[http://dx.doi.org/10.1042/BST0370937] [PMID: 19754430] 
[94] 
Jackson PK, Eldridge AG, Freed E, et al. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol  2000; 10(10): 429-39.
[http://dx.doi.org/10.1016/S0962-8924(00)01834-1] [PMID: 10998601] 
[95] 
Metzger MB, Hristova VA, Weissman AM. HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci  2012; 125(Pt 3): 531-7.
[http://dx.doi.org/10.1242/jcs.091777] [PMID: 22389392] 
[96] 
Plechanovová A, Jaffray EG, McMahon SA, et al. Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nat Struct Mol Biol  2011; 18(9): 1052-9.
[http://dx.doi.org/10.1038/nsmb.2108] [PMID: 21857666] 
[97] 
Budhidarmo R, Nakatani Y, Day CL. RINGs hold the key to ubiquitin transfer. Trends Biochem Sci  2012; 37(2): 58-65.
[http://dx.doi.org/10.1016/j.tibs.2011.11.001] [PMID: 22154517] 
[98] 
Plechanovová A, Jaffray EG, Tatham MH, Naismith JH, Hay RT. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature  2012; 489(7414): 115-20.
[http://dx.doi.org/10.1038/nature11376] [PMID: 22842904] 
[99] 
Huang X, Dixit VM. Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res  2016; 26(4): 484-98.
[http://dx.doi.org/10.1038/cr.2016.31] [PMID: 27002218] 
[100] 
Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature  2011; 474(7349): 105-8.
[http://dx.doi.org/10.1038/nature09966] [PMID: 21532592] 
[101] 
Smit JJ, Sixma TK. RBR E3-ligases at work. EMBO Rep  2014; 15(2): 142-54.
[http://dx.doi.org/10.1002/embr.201338166] [PMID: 24469331] 
[102] 
Dove KK, Klevit RE. RING-Between-RING E3 Ligases: emerging themes amid the variations. J Mol Biol  2017; 429(22): 3363-75.
[http://dx.doi.org/10.1016/j.jmb.2017.08.008] [PMID: 28827147] 
[103] 
Smit JJ, Monteferrario D, Noordermeer SM, van Dijk WJ, van der Reijden BA, Sixma TK. The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J  2012; 31(19): 3833-44.
[http://dx.doi.org/10.1038/emboj.2012.217] [PMID: 22863777] 
[104] 
Martino L, Brown NR, Masino L, et al. Determinants of E2-ubiquitin conjugate recognition by RBR E3 ligases. Sci Rep  2018; 8: 68.
[http://dx.doi.org/10.1038/s41598-017-18513-5] 
[105] 
Uchida C, Kitagawa M. RING-, HECT-, and RBR-type E3 ubiquitin ligases: involvement in human cancer. Curr Cancer Drug Targets  2016; 16(2): 157-74.
[http://dx.doi.org/10.2174/1568009616666151112122801] [PMID: 26560116] 
[106] 
Spratt DE, Walden H, Shaw GS. RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochem J  2014; 458(3): 421-37.
[http://dx.doi.org/10.1042/BJ20140006] [PMID: 24576094] 
[107] 
Marín I, Lucas JI, Gradilla AC, Ferrús A. Parkin and relatives: the RBR family of ubiquitin ligases. Physiol Genomics. 2004; 17(3): 253-63.
[http://dx.doi.org/10.1152/physiolgenomics.00226.2003] [PMID: 15152079] 
[108] 
Capili AD, Edghill EL, Wu K, Borden KL. Structure of the C-terminal RING finger from a RING-IBR-RING/TRIAD motif reveals a novel zinc-binding domain distinct from a RING. J Mol Biol  2004; 340(5): 1117-29.
[http://dx.doi.org/10.1016/j.jmb.2004.05.035] [PMID: 15236971] 
[109] 
Eisenhaber B, Chumak N, Eisenhaber F, et al. The ring between ring fingers (RBR) protein family Sci Rep 8. 
[110] 
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell  1990; 63(6): 1129-36.
[http://dx.doi.org/10.1016/0092-8674(90)90409-8] [PMID: 2175676] 
[111] 
Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J  1991; 10(13): 4129-35.
[http://dx.doi.org/10.1002/j.1460-2075.1991.tb04990.x] [PMID: 1661671] 
[112] 
Weber J, Polo S, Maspero E. HECT E3 ligases: A tale with multiple facets Frontiers in Physiology 10. 
[http://dx.doi.org/10.3389/fphys.2019.00370] 
[113] 
Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet  1997; 15(1): 70-3.
[http://dx.doi.org/10.1038/ng0197-70] [PMID: 8988171] 
[114] 
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell  1993; 75(3): 495-505.
[http://dx.doi.org/10.1016/0092-8674(93)90384-3] [PMID: 8221889] 
[115] 
Huibregtse JM, Scheffner M, Beaudenon S, Howley PM. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA  1995; 92(7): 2563-7.
[http://dx.doi.org/10.1073/pnas.92.7.2563] [PMID: 7708685] 
[116] 
Sluimer J, Distel B. Regulating the human HECT E3 ligases. Cell Mol Life Sci  2018; 75(17): 3121-41.
[http://dx.doi.org/10.1007/s00018-018-2848-2] [PMID: 29858610] 
[117] 
Amodio N, Scrima M, Palaia L, et al. Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas. Am J Pathol  2010; 177(5): 2622-34.
[http://dx.doi.org/10.2353/ajpath.2010.091075] [PMID: 20889565] 
[118] 
Beaudenon S, Huibregtse JM. HPV E6, E6AP and cervical cancer. BMC Biochem  2008; 9(Suppl. 1): S4.
[http://dx.doi.org/10.1186/1471-2091-9-S1-S4] 
[119] 
Bernassola F, Karin M, Ciechanover A, Melino G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell  2008; 14(1): 10-21.
[http://dx.doi.org/10.1016/j.ccr.2008.06.001] [PMID: 18598940] 
[120] 
Adhikary S, Marinoni F, Hock A, et al. The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell  2005; 123(3): 409-21.
[http://dx.doi.org/10.1016/j.cell.2005.08.016] [PMID: 16269333] 
[121] 
Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol  2009; 10(6): 398-409.
[http://dx.doi.org/10.1038/nrm2690] [PMID: 19436320] 
[122] 
Scheffner M, Kumar S. Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects. Biochim Biophys Acta  2014; 1843(1): 61-74.
[http://dx.doi.org/10.1016/j.bbamcr.2013.03.024] [PMID: 23545411] 
[123] 
Yang B, Kumar S. Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ  2010; 17(1): 68-77.
[http://dx.doi.org/10.1038/cdd.2009.84] [PMID: 19557014] 
[124] 
Nominé Y, Masson M, Charbonnier S, et al. Structural and functional analysis of E6 oncoprotein: insights in the molecular pathways of human papillomavirus-mediated pathogenesis. Mol Cell  2006; 21(5): 665-78.
[http://dx.doi.org/10.1016/j.molcel.2006.01.024] [PMID: 16507364] 
[125] 
Scheffner M, Staub O. HECT E3s and human disease BMC Biochemistry 2007; 8: 56.. 
[126] 
Wang M, Pickart CM. Different HECT domain ubiquitin ligases employ distinct mechanisms of polyubiquitin chain synthesis. EMBO J  2005; 24(24): 4324-33.
[http://dx.doi.org/10.1038/sj.emboj.7600895] [PMID: 16341092] 
[127] 
Fajner V, Maspero E, Polo S. Targeting HECT-type E3 ligases - insights from catalysis, regulation and inhibitors. FEBS Lett  2017; 591(17): 2636-47.
[http://dx.doi.org/10.1002/1873-3468.12775] [PMID: 28771691] 
[128] 
Maspero E, Mari S, Valentini E, et al. Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation. EMBO Rep  2011; 12(4): 342-9.
[http://dx.doi.org/10.1038/embor.2011.21] [PMID: 21399620] 
[129] 
Maspero E, Valentini E, Mari S, et al. Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming. Nat Struct Mol Biol  2013; 20(6): 696-701.
[http://dx.doi.org/10.1038/nsmb.2566] [PMID: 23644597] 
[130] 
Bernassola F, Chillemi G, Melino G. HECT-Type E3 ubiquitin ligases in cancer. Trends Biochem Sci  2019; 44(12): 1057-75.
[http://dx.doi.org/10.1016/j.tibs.2019.08.004] [PMID: 31610939] 
[131] 
Senft D, Qi J, Ronai ZA. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer  2018; 18(2): 69-88.
[http://dx.doi.org/10.1038/nrc.2017.105] [PMID: 29242641] 
[132] 
Lin DYW, Diao J, Zhou D, Chen J. Biochemical and structural studies of a HECT-like ubiquitin ligase from Escherichia coli O157:H7. J Biol Chem  2011; 286(1): 441-9.
[http://dx.doi.org/10.1074/jbc.M110.167643] [PMID: 20980253] 
[133] 
Shen M, Schmitt S, Buac D, Dou QP. Targeting the ubiquitin-proteasome system for cancer therapy. Expert Opin Ther Targets  2013; 17(9): 1091-108.
[http://dx.doi.org/10.1517/14728222.2013.815728] [PMID: 23822887] 
[134] 
Kumari N, Lee KK, Jha S. Targeting the ubiquitin proteasome system in cancerNeoplasm Available from: https://www.intechopen.com/books/neoplasm/targeting-the-ubiquitin-proteasome-system-in-cancer
[135] 
Chauhan D, Hideshima T, Mitsiades C, Richardson P, Anderson KC. Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther  2005; 4(4): 686-92.
[http://dx.doi.org/10.1158/1535-7163.MCT-04-0338] [PMID: 15827343] 
[136] 
Meng L, Mohan R, Kwok BHB, Elofsson M, Sin N, Crews CM. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci USA  1999; 96(18): 10403-8.
[http://dx.doi.org/10.1073/pnas.96.18.10403] [PMID: 10468620] 
[137] 
Jang HH. Regulation of protein degradation by proteasomes in cancer. J Cancer Prev  2018; 23(4): 153-61.
[http://dx.doi.org/10.15430/JCP.2018.23.4.153] [PMID: 30671397] 
[138] 
Fraile JM, Quesada V, Rodríguez D, Freije JM, López-Otín C. Deubiquitinases in cancer: new functions and therapeutic options. Oncogene  2012; 31(19): 2373-88.
[http://dx.doi.org/10.1038/onc.2011.443] [PMID: 21996736] 
[139] 
Bednash JS, Mallampalli RK. Targeting deubiquitinases in cancer.In: Walker JM, Ed.Methods in molecular biology.  US: Humana Press Inc. 2018; pp. 295-305.
[140] 
Wei R, Liu X, Yu W, et al. Deubiquitinases in cancer. Oncotarget  2015; 6(15): 12872-89.
[http://dx.doi.org/10.18632/oncotarget.3671] [PMID: 25972356] 
[141] 
Hoffmann O, Heubner M, Anlasik T, et al. Circulating 20S proteasome in patients with non-metastasized breast cancer. Anticancer Res  2011; 31(6): 2197-201.
[PMID: 21737641] 
[142] 
Morozov AV, Karpov VL. Proteasomes and several aspects of their heterogeneity relevant to cancer. Front Oncol  2019; 9: 761.
[http://dx.doi.org/10.3389/fonc.2019.00761] 
[143] 
Crawford LJ, Walker B, Irvine AE. Proteasome inhibitors in cancer therapy. J Cell Commun Signal  2011; 5(2): 101-10.
[http://dx.doi.org/10.1007/s12079-011-0121-7] [PMID: 21484190] 
[144] 
Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia  2002; 16(4): 433-43.
[http://dx.doi.org/10.1038/sj.leu.2402417] [PMID: 11960320] 
[145] 
Tsvetkov P, Adler J, Myers N, et al. Oncogenic addiction to high 26S proteasome level. Cell Death Dis  2018; 9: 773.
[http://dx.doi.org/10.1038/s41419-018-0806-4] 
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DOI https://dx.doi.org/10.2174/2212796814999200609131623	Print ISSN 2212-7968
Publisher Name Bentham Science Publisher	Online ISSN 1872-3136
Current Chemical Biology

Targeting Protein Degradation in Cancer Treatment

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