The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer

Azmi       Yerlikaya; Ertan       Kanbur; Bruce    A.    Stanley; Emrah       Tümer
doi:10.2174/1871520620666200811114159
Abstract

Background: The ubiquitin-proteasome pathway is involved in almost all cellular processes (cell cycle, gene transcription and translation, cell survival and apoptosis, cell metabolism and protein quality control) mainly through the specific degradation of the majority of intracellular proteins (>80%) or partial processing of transcription factors (e.g., NF-κB). A growing amount of evidence now indicates that epigenetic changes are also regulated by the ubiquitin-proteasome pathway. Recent studies indicate that epigenetic regulations are equally crucial for almost all biological processes as well as for pathological conditions such as tumorigenesis, as compared to non-epigenetic control mechanisms (i.e., genetic alterations or classical signal transduction pathways).
Objective: Here, we reviewed the recent work highlighting the interaction of the ubiquitin-proteasome pathway components (e.g., ubiquitin, E1, E2 and E3 enzymes and 26S proteasome) with epigenetic regulators (histone deacetylases, histone acetyltransferases and DNA methyltransferases).
Results: Alterations in the regulation of the ubiquitin-proteasome pathway have been discovered in many pathological conditions. For example, a 2- to 32-fold increase in proteasomal activity and/or subunits has been noted in primary breast cancer cells. Although proteasome inhibitors have been successfully applied in the treatment of hematological malignancies (e.g., multiple myeloma), the clinical efficacy of the proteasomal inhibition is limited in solid cancers. Interestingly, recent studies show that the ubiquitin-proteasome and epigenetic pathways intersect in a number of ways through the regulation of epigenetic marks (i.e., acetylation, methylation and ubiquitylation).
Conclusion: It is therefore believed that novel treatment strategies involving new generation ubiquitinproteasome pathway inhibitors combined with DNA methyltransferase, histone deacetylase or histone acetyltransferase inhibitors may produce more effective results with fewer adverse effects in cancer treatment as compared to standard chemotherapeutics in hematological as well as solid cancers.
Keywords: Bortezomib, cancer, epigenetics, histone deacetylase, proteasome, ubiquitin.
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[1] 
Lecker, S.H.; Goldberg, A.L.; Mitch, W.E. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J. Am. Soc. Nephrol.,  2006, 17(7), 1807-1819.
[http://dx.doi.org/10.1681/ASN.2006010083] [PMID: 16738015] 
[2] 
Meyer-Schwesinger, C. The ubiquitin-proteasome system in kidney physiology and disease. Nat. Rev. Nephrol.,  2019, 15(7), 393-411.
[http://dx.doi.org/10.1038/s41581-019-0148-1] [PMID: 31036905] 
[3] 
Chen, L.; Madura, K. Increased proteasome activity, ubiquitin-conjugating enzymes, and eEF1A translation factor detected in breast cancer tissue. Cancer Res.,  2005, 65(13), 5599-5606.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0201] [PMID: 15994932] 
[4] 
Narayanan, S.; Cai, C.Y.; Assaraf, Y.G.; Guo, H.Q.; Cui, Q.; Wei, L.; Huang, J.J.; Ashby, C.R., Jr; Chen, Z.S. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist. Updat.,  2020, 48100663
[http://dx.doi.org/10.1016/j.drup.2019.100663] [PMID: 31785545] 
[5] 
Roeten, M.S.F.; Cloos, J.; Jansen, G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother. Pharmacol.,  2018, 81(2), 227-243.
[http://dx.doi.org/10.1007/s00280-017-3489-0] [PMID: 29184971] 
[6] 
Li, C.; Wang, X.; Li, X.; Qiu, K.; Jiao, F.; Liu, Y.; Kong, Q.; Liu, Y.; Wu, Y. Proteasome inhibition activates autophagy-lysosome pathway associated with TFEB dephosphorylation and nuclear translocation. Front. Cell Dev. Biol.,  2019, 7, 170.
[http://dx.doi.org/10.3389/fcell.2019.00170] [PMID: 31508418] 
[7] 
Bach, S.V.; Hegde, A.N. The proteasome and epigenetics: Zooming in on histone modifications. Biomol. Concepts,  2016, 7(4), 215-227.
[http://dx.doi.org/10.1515/bmc-2016-0016] [PMID: 27522625] 
[8] 
Qian, M.X.; Pang, Y.; Liu, C.H.; Haratake, K.; Du, B.Y.; Ji, D.Y.; Wang, G.F.; Zhu, Q.Q.; Song, W.; Yu, Y.; Zhang, X.X.; Huang, H.T.; Miao, S.; Chen, L.B.; Zhang, Z.H.; Liang, Y.N.; Liu, S.; Cha, H.; Yang, D.; Zhai, Y.; Komatsu, T.; Tsuruta, F.; Li, H.; Cao, C.; Li, W.; Li, G.H.; Cheng, Y.; Chiba, T.; Wang, L.; Goldberg, A.L.; Shen, Y.; Qiu, X.B. Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell,  2013, 153(5), 1012-1024.
[http://dx.doi.org/10.1016/j.cell.2013.04.032] [PMID: 23706739] 
[9] 
Maze, I.; Wenderski, W.; Noh, K.M.; Bagot, R.C.; Tzavaras, N.; Purushothaman, I.; Elsässer, S.J.; Guo, Y.; Ionete, C.; Hurd, Y.L.; Tamminga, C.A.; Halene, T.; Farrelly, L.; Soshnev, A.A.; Wen, D.; Rafii, S.; Birtwistle, M.R.; Akbarian, S.; Buchholz, B.A.; Blitzer, R.D.; Nestler, E.J.; Yuan, Z.F.; Garcia, B.A.; Shen, L.; Molina, H.; Allis, C.D. Critical role of histone turnover in neuronal transcription and plasticity. Neuron,  2015, 87(1), 77-94.
[http://dx.doi.org/10.1016/j.neuron.2015.06.014] [PMID: 26139371] 
[10] 
Ezhkova, E.; Tansey, W.P. Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3. Mol. Cell,  2004, 13(3), 435-442.
[http://dx.doi.org/10.1016/S1097-2765(04)00026-7] [PMID: 14967150] 
[11] 
Kinyamu, H.K.; Archer, T.K. Proteasome activity modulates chromatin modifications and RNA polymerase II phosphorylation to enhance glucocorticoid receptor-mediated transcription. Mol. Cell. Biol.,  2007, 27(13), 4891-4904.
[http://dx.doi.org/10.1128/MCB.02162-06] [PMID: 17438138] 
[12] 
Kinyamu, H.K.; Jefferson, W.N.; Archer, T.K. Intersection of nuclear receptors and the proteasome on the epigenetic landscape. Environ. Mol. Mutagen.,  2008, 49(1), 83-95.
[http://dx.doi.org/10.1002/em.20360] [PMID: 18095329] 
[13] 
Gontan, C.; Achame, E.M.; Demmers, J.; Barakat, T.S.; Rentmeester, E.; van IJcken, W.; Grootegoed, J.A.; Gribnau, J. RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation. Nature,  2012, 485(7398), 386-390.
[http://dx.doi.org/10.1038/nature11070] [PMID: 22596162] 
[14] 
Wang, F.; Bach, I. Rlim/Rnf12, Rex1, and X chromosome inactivation. Front. Cell Dev. Biol.,  2019, 7, 258.
[http://dx.doi.org/10.3389/fcell.2019.00258] [PMID: 31737626] 
[15] 
Yerlikaya, A.; Yöntem, M. The significance of ubiquitin proteasome pathway in cancer development. Rec Patents Anticancer Drug Discov.,  2013, 8(3), 298-309.
[http://dx.doi.org/10.2174/1574891X113089990033] [PMID: 23061719] 
[16] 
Metzger, M.B.; Hristova, V.A.; Weissman, A.M. HECT and RING finger families of E3 ubiquitin ligases at a glance. J. Cell Sci.,  2012, 125(Pt 3), 531-537.
[http://dx.doi.org/10.1242/jcs.091777] [PMID: 22389392] 
[17] 
Sluimer, J.; Distel, B. Regulating the human HECT E3 ligases. Cell. Mol. Life Sci.,  2018, 75(17), 3121-3141.
[http://dx.doi.org/10.1007/s00018-018-2848-2] [PMID: 29858610] 
[18] 
Guharoy, M.; Bhowmick, P.; Sallam, M.; Tompa, P. Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system. Nat. Commun.,  2016, 7, 10239.
[http://dx.doi.org/10.1038/ncomms10239] [PMID: 26732515] 
[19] 
Thibaudeau, T.A.; Smith, D.M. A practical review of proteasome pharmacology. Pharmacol. Rev.,  2019, 71(2), 170-197.
[http://dx.doi.org/10.1124/pr.117.015370] [PMID: 30867233] 
[20] 
Rock, K.L.; Gramm, C.; Rothstein, L.; Clark, K.; Stein, R.; Dick, L.; Hwang, D.; Goldberg, A.L. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell,  1994, 78(5), 761-771.
[http://dx.doi.org/10.1016/S0092-8674(94)90462-6] [PMID: 8087844] 
[21] 
Hough, R.; Pratt, G.; Rechsteiner, M. Purification of two high molecular weight proteases from rabbit reticulocyte lysate. J. Biol. Chem.,  1987, 262(17), 8303-8313.
[PMID: 3298229] 
[22] 
Hough, R.; Rechsteiner, M. Ubiquitin-lysozyme conjugates. Purification and susceptibility to proteolysis. J. Biol. Chem.,  1986, 261(5), 2391-2399.
[PMID: 3003113] 
[23] 
Chen, S.; Wu, J.; Lu, Y.; Ma, Y.B.; Lee, B.H.; Yu, Z.; Ouyang, Q.; Finley, D.J.; Kirschner, M.W.; Mao, Y. Structural basis for dynamic regulation of the human 26S proteasome. Proc. Natl. Acad. Sci. USA,  2016, 113(46), 12991-12996.
[http://dx.doi.org/10.1073/pnas.1614614113] [PMID: 27791164] 
[24] 
Dong, Y.; Zhang, S.; Wu, Z.; Li, X.; Wang, W.L.; Zhu, Y.; Stoilova-McPhie, S.; Lu, Y.; Finley, D.; Mao, Y. Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome. Nature,  2019, 565(7737), 49-55.
[http://dx.doi.org/10.1038/s41586-018-0736-4] [PMID: 30479383] 
[25] 
Luan, B.; Huang, X.; Wu, J.; Mei, Z.; Wang, Y.; Xue, X.; Yan, C.; Wang, J.; Finley, D.J.; Shi, Y.; Wang, F. Structure of an endogenous yeast 26S proteasome reveals two major conformational states. Proc. Natl. Acad. Sci. USA,  2016, 113(10), 2642-2647.
[http://dx.doi.org/10.1073/pnas.1601561113] [PMID: 26929360] 
[26] 
Voges, D.; Zwickl, P.; Baumeister, W. The 26S proteasome: A molecular machine designed for controlled proteolysis. Annu. Rev. Biochem.,  1999, 68, 1015-1068.
[http://dx.doi.org/10.1146/annurev.biochem.68.1.1015] [PMID: 10872471] 
[27] 
Zwickl, P.; Voges, D.; Baumeister, W. The proteasome: a macromolecular assembly designed for controlled proteolysis. Philos. Trans. R. Soc. Lond. B Biol. Sci.,  1999, 354(1389), 1501-1511.
[http://dx.doi.org/10.1098/rstb.1999.0494] [PMID: 10582236] 
[28] 
Pang, Y.Y.; Lu, R.J.H.; Chen, P.Y. Behavioral epigenetics: perspectives based on experience-dependent epigenetic inheritance Epigenomes,  2019, 3(3)
[http://dx.doi.org/10.3390/epigenomes3030018] 
[29] 
Peng, J.C.; Karpen, G.H. Epigenetic regulation of heterochromatic DNA stability. Curr. Opin. Genet. Dev.,  2008, 18(2), 204-211.
[http://dx.doi.org/10.1016/j.gde.2008.01.021] [PMID: 18372168] 
[30] 
Bach, I. Releasing the break on X chromosome inactivation: Rnf12/RLIM targets REX1 for degradation. Cell Res.,  2012, 22(11), 1524-1526.
[http://dx.doi.org/10.1038/cr.2012.98] [PMID: 22785560] 
[31] 
Morey, C.; Avner, P. Genetics and epigenetics of the X chromosome. Ann. N. Y. Acad. Sci.,  2010, 1214, E18-E33.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05943.x] [PMID: 21382199] 
[32] 
Brockdorff, N. Localized accumulation of Xist RNA in X chromosome inactivation. Open Biol.,  2019, 9(12)190213
[http://dx.doi.org/10.1098/rsob.190213] [PMID: 31795917] 
[33] 
Jeon, Y.; Sarma, K.; Lee, J.T. New and Xisting regulatory mechanisms of X chromosome inactivation. Curr. Opin. Genet. Dev.,  2012, 22(2), 62-71.
[http://dx.doi.org/10.1016/j.gde.2012.02.007] [PMID: 22424802] 
[34] 
Zeng, Y.T.; Liu, X.F.; Yang, W.T.; Zheng, P.S. REX1 promotes EMT-induced cell metastasis by activating the JAK2/STAT3-signaling pathway by targeting SOCS1 in cervical cancer. Oncogene,  2019, 38(43), 6940-6957.
[http://dx.doi.org/10.1038/s41388-019-0906-3] [PMID: 31409905] 
[35] 
Feinberg, A.P.; Ohlsson, R.; Henikoff, S. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet.,  2006, 7(1), 21-33.
[http://dx.doi.org/10.1038/nrg1748] [PMID: 16369569] 
[36] 
Mirabella, A.C.; Foster, B.M.; Bartke, T. Chromatin deregulation in disease. Chromosoma,  2016, 125(1), 75-93.
[http://dx.doi.org/10.1007/s00412-015-0530-0] [PMID: 26188466] 
[37] 
Baylin, S.B.; Jones, P.A. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol.,  2016, 8(9)a019505
[http://dx.doi.org/10.1101/cshperspect.a019505] [PMID: 27194046] 
[38] 
Asada, S.; Fujino, T.; Goyama, S.; Kitamura, T. The role of ASXL1 in hematopoiesis and myeloid malignancies. Cell. Mol. Life Sci.,  2019, 76(13), 2511-2523.
[http://dx.doi.org/10.1007/s00018-019-03084-7] [PMID: 30927018] 
[39] 
Duchmann, M.; Itzykson, R. Clinical update on hypomethylating agents. Int. J. Hematol.,  2019, 110(2), 161-169.
[http://dx.doi.org/10.1007/s12185-019-02651-9] [PMID: 31020568] 
[40] 
Ghoshal, K.; Datta, J.; Majumder, S.; Bai, S.; Kutay, H.; Motiwala, T.; Jacob, S.T. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol. Cell. Biol.,  2005, 25(11), 4727-4741.
[http://dx.doi.org/10.1128/MCB.25.11.4727-4741.2005] [PMID: 15899874] 
[41] 
Lawrence, M.; Daujat, S.; Schneider, R. Lateral thinking: How histone modifications regulate gene expression. Trends Genet.,  2016, 32(1), 42-56.
[http://dx.doi.org/10.1016/j.tig.2015.10.007] [PMID: 26704082] 
[42] 
Kinyamu, H.K.; Chen, J.; Archer, T.K. Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J. Mol. Endocrinol.,  2005, 34(2), 281-297.
[http://dx.doi.org/10.1677/jme.1.01680] [PMID: 15821097] 
[43] 
West, M.H.; Bonner, W.M. Histone 2B can be modified by the attachment of ubiquitin. Nucleic Acids Res.,  1980, 8(20), 4671-4680.
[http://dx.doi.org/10.1093/nar/8.20.4671] [PMID: 6255427] 
[44] 
West, M.H.; Bonner, W.M. Histone 2A, a heteromorphous family of eight protein species. Biochemistry,  1980, 19(14), 3238-3245.
[http://dx.doi.org/10.1021/bi00555a022] [PMID: 7407044] 
[45] 
Osley, M.A.; Fleming, A.B.; Kao, C.F. Histone ubiquitylation and the regulation of transcription. Results Probl. Cell Differ.,  2006, 41, 47-75.
[http://dx.doi.org/10.1007/400_006] [PMID: 16909890] 
[46] 
Wang, H.; Zhai, L.; Xu, J.; Joo, H.Y.; Jackson, S.; Erdjument-Bromage, H.; Tempst, P.; Xiong, Y.; Zhang, Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol. Cell,  2006, 22(3), 383-394.
[http://dx.doi.org/10.1016/j.molcel.2006.03.035] [PMID: 16678110] 
[47] 
Emre, N.C.; Berger, S.L. Histone H2B ubiquitylation and deubiquitylation in genomic regulation. Cold Spring Harb. Symp. Quant. Biol.,  2004, 69, 289-299.
[http://dx.doi.org/10.1101/sqb.2004.69.289] [PMID: 16117661] 
[48] 
Meas, R.; Mao, P. Histone ubiquitylation and its roles in transcription and DNA damage response. DNA Repair (Amst.),  2015, 36, 36-42.
[http://dx.doi.org/10.1016/j.dnarep.2015.09.016] [PMID: 26422137] 
[49] 
Fleming, A.B.; Kao, C.F.; Hillyer, C.; Pikaart, M.; Osley, M.A. H2B ubiquitylation plays a role in nucleosome dynamics during transcription elongation. Mol. Cell,  2008, 31(1), 57-66.
[http://dx.doi.org/10.1016/j.molcel.2008.04.025] [PMID: 18614047] 
[50] 
Henry, K.W.; Wyce, A.; Lo, W.S.; Duggan, L.J.; Emre, N.C.; Kao, C.F.; Pillus, L.; Shilatifard, A.; Osley, M.A.; Berger, S.L. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev.,  2003, 17(21), 2648-2663.
[http://dx.doi.org/10.1101/gad.1144003] [PMID: 14563679] 
[51] 
Nelson, D.M.; Ye, X.; Hall, C.; Santos, H.; Ma, T.; Kao, G.D.; Yen, T.J.; Harper, J.W.; Adams, P.D. Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity. Mol. Cell. Biol.,  2002, 22(21), 7459-7472.
[http://dx.doi.org/10.1128/MCB.22.21.7459-7472.2002] [PMID: 12370293] 
[52] 
Lengauer, C.; Kinzler, K.W.; Vogelstein, B. Genetic instabilities in human cancers. Nature,  1998, 396(6712), 643-649.
[http://dx.doi.org/10.1038/25292] [PMID: 9872311] 
[53] 
Singh, R.K.; Kabbaj, M.H.; Paik, J.; Gunjan, A. Histone levels are regulated by phosphorylation and ubiquitylation-dependent proteolysis. Nat. Cell Biol.,  2009, 11(8), 925-933.
[http://dx.doi.org/10.1038/ncb1903] [PMID: 19578373] 
[54] 
Chandrasekharan, M.B.; Huang, F.; Sun, Z.W. Ubiquitination of histone H2B regulates chromatin dynamics by enhancing nucleosome stability. Proc. Natl. Acad. Sci. USA,  2009, 106(39), 16686-16691.
[http://dx.doi.org/10.1073/pnas.0907862106] [PMID: 19805358] 
[55] 
Tan, M.K.; Lim, H.J.; Harper, J.W. SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation. Mol. Cell. Biol.,  2011, 31(18), 3687-3699.
[http://dx.doi.org/10.1128/MCB.05746-11] [PMID: 21768309] 
[56] 
Nathan, D.; Ingvarsdottir, K.; Sterner, D.E.; Bylebyl, G.R.; Dokmanovic, M.; Dorsey, J.A.; Whelan, K.A.; Krsmanovic, M.; Lane, W.S.; Meluh, P.B.; Johnson, E.S.; Berger, S.L. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev.,  2006, 20(8), 966-976.
[http://dx.doi.org/10.1101/gad.1404206] [PMID: 16598039] 
[57] 
Shiio, Y.; Eisenman, R.N. Histone sumoylation is associated with transcriptional repression. Proc. Natl. Acad. Sci. USA,  2003, 100(23), 13225-13230.
[http://dx.doi.org/10.1073/pnas.1735528100] [PMID: 14578449] 
[58] 
Xia, Y.; Yang, W.; Fa, M.; Li, X.; Wang, Y.; Jiang, Y.; Zheng, Y.; Lee, J.H.; Li, J.; Lu, Z. RNF8 mediates histone H3 ubiquitylation and promotes glycolysis and tumorigenesis. J. Exp. Med.,  2017, 214(6), 1843-1855.
[http://dx.doi.org/10.1084/jem.20170015] [PMID: 28507061] 
[59] 
Lai, Y.; Li, J.; Li, X.; Zou, C. Lipopolysaccharide modulates p300 and Sirt1 to promote PRMT1 stability via an SCFFbxl17-recognized acetyldegron. J. Cell Sci.,  2017, 130(20), 3578-3587.
[http://dx.doi.org/10.1242/jcs.206904] [PMID: 28883095] 
[60] 
Brouillard, F.; Cremisi, C.E. Concomitant increase of histone acetyltransferase activity and degradation of p300 during retinoic acid-induced differentiation of F9 cells. J. Biol. Chem.,  2003, 278(41), 39509-39516.
[http://dx.doi.org/10.1074/jbc.M307123200] [PMID: 12888559] 
[61] 
Jones, S.; Wang, T.L.; Shih, I.M.; Mao, T.L.; Nakayama, K.; Roden, R.; Glas, R.; Slamon, D.; Diaz, L.A., Jr; Vogelstein, B.; Kinzler, K.W.; Velculescu, V.E.; Papadopoulos, N. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science,  2010, 330(6001), 228-231.
[http://dx.doi.org/10.1126/science.1196333] [PMID: 20826764] 
[62] 
Guan, B.; Gao, M.; Wu, C.H.; Wang, T.L.; Shih, I.M. Functional analysis of in-frame indel ARID1A mutations reveals new regulatory mechanisms of its tumor suppressor functions. Neoplasia,  2012, 14(10), 986-993.
[http://dx.doi.org/10.1593/neo.121218] [PMID: 23097632] 
[63] 
Bird, A. Perceptions of epigenetics. Nature,  2007, 447(7143), 396-398.
[http://dx.doi.org/10.1038/nature05913] [PMID: 17522671] 
[64] 
Llinàs-Arias, P.; Esteller, M. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: An update. Open Biol.,  2017, 7(9)170152
[http://dx.doi.org/10.1098/rsob.170152] [PMID: 28931650] 
[65] 
Du, Z.; Song, J.; Wang, Y.; Zhao, Y.; Guda, K.; Yang, S.; Kao, H.Y.; Xu, Y.; Willis, J.; Markowitz, S.D.; Sedwick, D.; Ewing, R.M.; Wang, Z. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci. Signal.,  2010, 3(146), ra80.
[http://dx.doi.org/10.1126/scisignal.2001462] [PMID: 21045206] 
[66] 
Frank, S.R.; Parisi, T.; Taubert, S.; Fernandez, P.; Fuchs, M.; Chan, H.M.; Livingston, D.M.; Amati, B. MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep.,  2003, 4(6), 575-580.
[http://dx.doi.org/10.1038/sj.embor.embor861] [PMID: 12776177] 
[67] 
Ambrosio, S.; Amente, S.; Saccà, C.D.; Capasso, M.; Calogero, R.A.; Lania, L.; Majello, B. LSD1 mediates MYCN control of epithelial-mesenchymal transition through silencing of metastatic suppressor NDRG1 gene. Oncotarget,  2017, 8(3), 3854-3869.
[http://dx.doi.org/10.18632/oncotarget.12924] [PMID: 27894074] 
[68] 
Amente, S.; Milazzo, G.; Sorrentino, M.C.; Ambrosio, S.; Di Palo, G.; Lania, L.; Perini, G.; Majello, B. Lysine-Specific Demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma. Oncotarget,  2015, 6(16), 14572-14583.
[http://dx.doi.org/10.18632/oncotarget.3990] [PMID: 26062444] 
[69] 
Ambrosio, S.; Majello, B. Targeting histone demethylase LSD1/KDM1a in neurodegenerative diseases. J. Exp. Neurosci.,  2018, 121179069518765743
[http://dx.doi.org/10.1177/1179069518765743] [PMID: 29581704] 
[70] 
Anan, K.; Hino, S.; Shimizu, N.; Sakamoto, A.; Nagaoka, K.; Takase, R.; Kohrogi, K.; Araki, H.; Hino, Y.; Usuki, S.; Oki, S.; Tanaka, H.; Nakamura, K.; Endo, F.; Nakao, M. LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation. Nucleic Acids Res.,  2018, 46(11), 5441-5454.
[http://dx.doi.org/10.1093/nar/gky234] [PMID: 29618057] 
[71] 
Egolf, S.; Aubert, Y.; Doepner, M.; Anderson, A.; Maldonado-Lopez, A.; Pacella, G.; Lee, J.; Ko, E.K.; Zou, J.; Lan, Y. LSD1 inhibition promotes epithelial differentiation through derepression of fate-determining transcription factors. Cell Rep.,  2019, 28(8), 1981-1992.
[http://dx.doi.org/10.1016/j.celrep.2019.07.058] 
[72] 
Sehrawat, A.; Gao, L.; Wang, Y.; Bankhead, A., III; McWeeney, S.K.; King, C.J.; Schwartzman, J.; Urrutia, J.; Bisson, W.H.; Coleman, D.J.; Joshi, S.K.; Kim, D.H.; Sampson, D.A.; Weinmann, S.; Kallakury, B.V.S.; Berry, D.L.; Haque, R.; Van Den Eeden, S.K.; Sharma, S.; Bearss, J.; Beer, T.M.; Thomas, G.V.; Heiser, L.M.; Alumkal, J.J. LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc. Natl. Acad. Sci. USA,  2018, 115(18), E4179-E4188.
[http://dx.doi.org/10.1073/pnas.1719168115] [PMID: 29581250] 
[73] 
Wang, Z.; Long, Q.Y.; Chen, L.; Fan, J.D.; Wang, Z.N.; Li, L.Y.; Wu, M.; Chen, X. Inhibition of H3K4 demethylation induces autophagy in cancer cell lines. Biochim. Biophys. Acta Mol. Cell Res.,  2017, 1864(12), 2428-2437.
[http://dx.doi.org/10.1016/j.bbamcr.2017.08.005] [PMID: 28800922] 
[74] 
Lin, Y.; Wu, Y.; Li, J.; Dong, C.; Ye, X.; Chi, Y.I.; Evers, B.M.; Zhou, B.P. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J.,  2010, 29(11), 1803-1816.
[http://dx.doi.org/10.1038/emboj.2010.63] [PMID: 20389281] 
[75] 
Liu, J.; Feng, J.; Li, L.; Lin, L.; Ji, J.; Lin, C.; Liu, L.; Zhang, N.; Duan, D.; Li, Z.; Huang, B.; Zhang, Y.; Lu, J. Arginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancer. EMBO Rep.,  2020, 21(2)e48597
[http://dx.doi.org/10.15252/embr.201948597] [PMID: 31833203] 
[76] 
Yi, L.; Cui, Y.; Xu, Q.; Jiang, Y. Stabilization of LSD1 by deubiquitinating enzyme USP7 promotes glioblastoma cell tumorigenesis and metastasis through suppression of the p53 signaling pathway. Oncol. Rep.,  2016, 36(5), 2935-2945.
[http://dx.doi.org/10.3892/or.2016.5099] [PMID: 27632941] 
[77] 
Zou, C.; Mallampalli, R.K. Regulation of histone modifying enzymes by the ubiquitin-proteasome system. Biochim. Biophys. Acta,  2014, 1843(4), 694-702.
[http://dx.doi.org/10.1016/j.bbamcr.2013.12.016] [PMID: 24389248] 
[78] 
Suchánková, J.; Legartová, S.; Sehnalová, P.; Kozubek, S.; Valente, S.; Labella, D.; Mai, A.; Eckerich, C.; Fackelmayer, F.O.; Sorokin, D.V.; Bartova, E. PRMT1 arginine methyltransferase accumulates in cytoplasmic bodies that respond to selective inhibition and DNA damage. Eur. J. Histochem.,  2014, 58(2), 2389.
[http://dx.doi.org/10.4081/ejh.2014.2389] [PMID: 24998928] 
[79] 
Tsilimigras, D.I.; Ntanasis-Stathopoulos, I.; Moris, D.; Spartalis, E.; Pawlik, T.M. Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective. Surg. Oncol.,  2018, 27(4), 611-618.
[http://dx.doi.org/10.1016/j.suronc.2018.07.015] [PMID: 30449480] 
[80] 
Glozak, M.A.; Seto, E. Histone deacetylases and cancer. Oncogene,  2007, 26(37), 5420-5432.
[http://dx.doi.org/10.1038/sj.onc.1210610] [PMID: 17694083] 
[81] 
Damaskos, C.; Garmpis, N.; Valsami, S.; Kontos, M.; Spartalis, E.; Kalampokas, T.; Kalampokas, E.; Athanasiou, A.; Moris, D.; Daskalopoulou, A.; Davakis, S.; Tsourouflis, G.; Kontzoglou, K.; Perrea, D.; Nikiteas, N.; Dimitroulis, D. Histone deacetylase inhibitors: an attractive therapeutic strategy against breast cancer. Anticancer Res.,  2017, 37(1), 35-46.
[http://dx.doi.org/10.21873/anticanres.11286] [PMID: 28011471] 
[82] 
Seto, E.; Yoshida, M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol.,  2014, 6(4)a018713
[http://dx.doi.org/10.1101/cshperspect.a018713] [PMID: 24691964] 
[83] 
Kim, H.J.; Bae, S.C. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am. J. Transl. Res.,  2011, 3(2), 166-179.
[PMID: 21416059] 
[84] 
Pei, X.Y.; Dai, Y.; Grant, S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin. Cancer Res.,  2004, 10(11), 3839-3852.
[http://dx.doi.org/10.1158/1078-0432.CCR-03-0561] [PMID: 15173093] 
[85] 
Yuan, X.G.; Huang, Y.R.; Yu, T.; Jiang, H.W.; Xu, Y.; Zhao, X.Y. Chidamide, a histone deacetylase inhibitor, induces growth arrest and apoptosis in multiple myeloma cells in a caspase-dependent manner. Oncol. Lett.,  2019, 18(1), 411-419.
[http://dx.doi.org/10.3892/ol.2019.10301] [PMID: 31289512] 
[86] 
Guan, X. Cancer metastases: Challenges and opportunities. Acta Pharm. Sin. B,  2015, 5(5), 402-418.
[http://dx.doi.org/10.1016/j.apsb.2015.07.005] [PMID: 26579471] 
[87] 
Lyu, Y.; Xiao, Q.; Li, Y.; Wu, Y.; He, W.; Yin, L. “Locked” cancer cells are more sensitive to chemotherapy. Bioeng. Transl. Med.,  2019, 4(2)e10130
[http://dx.doi.org/10.1002/btm2.10130] [PMID: 31249880] 
[88] 
Yerlikaya, A.; Okur, E. An investigation of the mechanisms underlying the proteasome inhibitor bortezomib resistance in PC3 prostate cancer cell line. Cytotechnology,  2020, 72(1), 121-130.
[http://dx.doi.org/10.1007/s10616-019-00362-x] [PMID: 31863311] 
[89] 
Brünnert, D.; Kraus, M.; Stühmer, T.; Kirner, S.; Heiden, R.; Goyal, P.; Driessen, C.; Bargou, R.C.; Chatterjee, M. Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma. Biochim. Biophys. Acta Mol. Basis Dis.,  2019, 1865(6), 1666-1676.
[http://dx.doi.org/10.1016/j.bbadis.2019.04.003] [PMID: 30954557] 
[90] 
Brayer, J.; Baz, R. The potential of ixazomib, a second-generation proteasome inhibitor, in the treatment of multiple myeloma. Ther. Adv. Hematol.,  2017, 8(7), 209-220.
[http://dx.doi.org/10.1177/2040620717710171] [PMID: 28694935] 
[91] 
Ma, Y.; Liu, W.; Zhang, L.; Jia, G. Effects of histone deacetylase inhibitor panobinostat (LBH589) on bone marrow mononuclear cells of relapsed or refractory multiple myeloma patients and its mechanisms. Med. Sci. Monit.,  2017, 23, 5150-5157.
[http://dx.doi.org/10.12659/MSM.904232] [PMID: 29080899] 
[92] 
Zhou, X.; Hao, Q.; Lu, H. Mutant p53 in cancer therapy-the barrier or the path. J. Mol. Cell Biol.,  2019, 11(4), 293-305.
[http://dx.doi.org/10.1093/jmcb/mjy072] [PMID: 30508182] 
[93] 
Meng, X.; Yang, S.; Li, Y.; Li, Y.; Devor, E.J.; Bi, J.; Wang, X.; Umesalma, S.; Quelle, D.E.; Thiel, W.H.; Thiel, K.W.; Leslie, K.K. Combination of proteasome and histone deacetylase inhibitors overcomes the impact of gain-of-function p53 mutations. Dis. Markers,  2018, 20183810108
[http://dx.doi.org/10.1155/2018/3810108] [PMID: 30647797] 
[94] 
Ozaki, T.; Nakagawara, A. role of p53 in cell death and human cancers. Cancers (Basel),  2011, 3(1), 994-1013.
[http://dx.doi.org/10.3390/cancers3010994] [PMID: 24212651] 
[95] 
Yazbeck, V.; Shafer, D.; Perkins, E.B.; Coppola, D.; Sokol, L.; Richards, K.L.; Shea, T.; Ruan, J.; Parekh, S.; Strair, R. A phase II trial of bortezomib and vorinostat in mantle cell lymphoma and diffuse large B-cell lymphoma. Clin. Lymphoma Myeloma Leuk.,  2018, 18(9), 569-575.
[96] 
Cortés, C.; Kozma, S.C.; Tauler, A.; Ambrosio, S. MYCN concurrence with SAHA-induced cell death in human neuroblastoma cells. Cell Oncol. (Dordr.),  2015, 38(5), 341-352.
[http://dx.doi.org/10.1007/s13402-015-0233-9] [PMID: 26306783] 
[97] 
Dzieran, J.; Rodriguez Garcia, A.; Westermark, U.K.; Henley, A.B.; Eyre Sánchez, E.; Träger, C.; Johansson, H.J.; Lehtiö, J.; Arsenian-Henriksson, M. MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling. Proc. Natl. Acad. Sci. USA,  2018, 115(6), E1229-E1238.
[http://dx.doi.org/10.1073/pnas.1710901115] [PMID: 29374092] 
[98] 
Folkerts, H.; Hilgendorf, S.; Vellenga, E.; Bremer, E.; Wiersma, V.R. The multifaceted role of autophagy in cancer and the microenvironment. Med. Res. Rev.,  2019, 39(2), 517-560.
[http://dx.doi.org/10.1002/med.21531] [PMID: 30302772] 
[99] 
Kaliszczak, M.; van Hechanova, E.; Li, Y.; Alsadah, H.; Parzych, K.; Auner, H.W.; Aboagye, E.O. The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death. Br. J. Cancer,  2018, 119(10), 1278-1287.
[http://dx.doi.org/10.1038/s41416-018-0232-5] [PMID: 30318510] 
[100] 
Kaliszczak, M.; Trousil, S.; Åberg, O.; Perumal, M.; Nguyen, Q.D.; Aboagye, E.O. A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth. Br. J. Cancer,  2013, 108(2), 342-350.
[http://dx.doi.org/10.1038/bjc.2012.576] [PMID: 23322205] 
[101] 
Rey, M.; Irondelle, M.; Waharte, F.; Lizarraga, F.; Chavrier, P. HDAC6 is required for invadopodia activity and invasion by breast tumor cells. Eur. J. Cell Biol.,  2011, 90(2-3), 128-135.
[http://dx.doi.org/10.1016/j.ejcb.2010.09.004] [PMID: 20970878] 
[102] 
Sakuma, T.; Uzawa, K.; Onda, T.; Shiiba, M.; Yokoe, H.; Shibahara, T.; Tanzawa, H. Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Int. J. Oncol.,  2006, 29(1), 117-124.
[http://dx.doi.org/10.3892/ijo.29.1.117] [PMID: 16773191] 
[103] 
Jung, K.H.; Noh, J.H.; Kim, J.K.; Eun, J.W.; Bae, H.J.; Chang, Y.G.; Kim, M.G.; Park, W.S.; Lee, J.Y.; Lee, S.Y.; Chu, I.S.; Nam, S.W. Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-terminal kinase-mediated beclin 1-dependent autophagic cell death in liver cancer. Hepatology,  2012, 56(2), 644-657.
[http://dx.doi.org/10.1002/hep.25699] [PMID: 22392728] 
[104] 
Anagnostou, V.K.; Brahmer, J.R. Cancer immunotherapy: A future paradigm shift in the treatment of non-small cell lung cancer. Clin. Cancer Res.,  2015, 21(5), 976-984.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1187] [PMID: 25733707] 
[105] 
Santo, L.; Hideshima, T.; Kung, A.L.; Tseng, J.C.; Tamang, D.; Yang, M.; Jarpe, M.; van Duzer, J.H.; Mazitschek, R.; Ogier, W.C.; Cirstea, D.; Rodig, S.; Eda, H.; Scullen, T.; Canavese, M.; Bradner, J.; Anderson, K.C.; Jones, S.S.; Raje, N. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood,  2012, 119(11), 2579-2589.
[http://dx.doi.org/10.1182/blood-2011-10-387365] [PMID: 22262760] 
[106] 
Raje, N.; Hari, P.N.; Vogl, D.T.; Jagannath, S.; Orlowski, R.Z.; Supko, J.G.; Stephenson, P.; Jones, S.S.; Wheeler, C.; Lonial, S. Rocilinostat (ACY-1215), a selective HDAC6 inhibitor, alone and in combination with bortezomib in multiple myeloma: preliminary results from the first-in-humans phase I/II study. Blood,  2012, 120, 21.
[http://dx.doi.org/10.1182/blood.V120.21.4061.4061] 
[107] 
Vogl, D.T.; Raje, N.; Jagannath, S.; Richardson, P.; Hari, P.; Orlowski, R.; Supko, J.G.; Tamang, D.; Yang, M.; Jones, S.S.; Wheeler, C.; Markelewicz, R.J.; Lonial, S. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin. Cancer Res.,  2017, 23(13), 3307-3315.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-2526] [PMID: 28053023] 
[108] 
Yee, A.J.; Bensinger, W.I.; Supko, J.G.; Voorhees, P.M.; Berdeja, J.G.; Richardson, P.G.; Libby, E.N.; Wallace, E.E.; Birrer, N.E.; Burke, J.N.; Tamang, D.L.; Yang, M.; Jones, S.S.; Wheeler, C.A.; Markelewicz, R.J.; Raje, N.S. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A multicentre phase 1b trial. Lancet Oncol.,  2016, 17(11), 1569-1578.
[http://dx.doi.org/10.1016/S1470-2045(16)30375-8] [PMID: 27646843] 
[109] 
Bae, J.; Hideshima, T.; Tai, Y.T.; Song, Y.; Richardson, P.; Raje, N.; Munshi, N.C.; Anderson, K.C. Histone Deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors. Leukemia,  2018, 32(9), 1932-1947.
[http://dx.doi.org/10.1038/s41375-018-0062-8] [PMID: 29487385] 
[110] 
Hideshima, T.; Qi, J.; Paranal, R.M.; Tang, W.; Greenberg, E.; West, N.; Colling, M.E.; Estiu, G.; Mazitschek, R.; Perry, J.A.; Ohguchi, H.; Cottini, F.; Mimura, N.; Görgün, G.; Tai, Y.T.; Richardson, P.G.; Carrasco, R.D.; Wiest, O.; Schreiber, S.L.; Anderson, K.C.; Bradner, J.E. Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc. Natl. Acad. Sci. USA,  2016, 113(46), 13162-13167.
[http://dx.doi.org/10.1073/pnas.1608067113] [PMID: 27799547] 
[111] 
Hideshima, T.; Mazitschek, R.; Qi, J.; Mimura, N.; Tseng, J.C.; Kung, A.L.; Bradner, J.E.; Anderson, K.C. HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer. Oncotarget,  2017, 8(46), 80109-80123.
[http://dx.doi.org/10.18632/oncotarget.19019] [PMID: 29113288] 
[112] 
Besse, L.; Kraus, M.; Besse, A.; Bader, J.; Silzle, T.; Mehrling, T.; Driessen, C. The first-in-class alkylating HDAC inhibitor EDO-S101 is highly synergistic with proteasome inhibition against multiple myeloma through activation of multiple pathways. Blood Cancer J.,  2017, 7(7)e589
[http://dx.doi.org/10.1038/bcj.2017.69] [PMID: 28753594] 
[113] 
Cosenza, M.; Pozzi, S. The therapeutic strategy of HDAC6 inhibitors in lymphoproliferative disease. Int. J. Mol. Sci.,  2018, 19(8)E2337
[http://dx.doi.org/10.3390/ijms19082337] [PMID: 30096875] 
[114] 
Stebbing, J.; Bower, M.; Syed, N.; Smith, P.; Yu, V.; Crook, T. Epigenetics: An emerging technology in the diagnosis and treatment of cancer. Pharmacogenomics,  2006, 7(5), 747-757.
[http://dx.doi.org/10.2217/14622416.7.5.747] [PMID: 16886899] 
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DOI https://dx.doi.org/10.2174/1871520620666200811114159	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992
Anti-Cancer Agents in Medicinal Chemistry

The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer

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