Abstract
Epigenetics refers to alterations in the chromatin that regulate gene expression without changing the nucleotide sequence of DNA. An “epigenetic code” constituted by DNA methylation and different posttranslational modifications of histone proteins is crucial for the regulation of gene expression status in various cells. Maintenance of cellular identity and differentiation in a specific developmental context is regulated through maintenance of the chromatin structure of the cells. This process involves both genetic and epigenetic mechanisms. There is emerging evidence that defects in epigenetic regulation are often observed in human cancer. The reversibility of epigenetic modifications and an improved understanding of epigenetic aberrations in the etiology of cancer promise identification of novel drug targets and development of epigenetic-based therapeutic avenues for cancer. Many such compounds that target chromatin-associated proteins and proteins involved in epigenetic regulation are currently under preclinical and clinical trials. In this chapter, we have summarized the discoveries of epigenetic-based therapies for cancer and highlighted the advancement in this field that provides a new future perspective.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Alpini G, Glaser SS, Zhang JP, Francis H, Han Y, Gong J, Stokes A, Francis T, Hughart N, Hubble L, Zhuang SM, Meng F (2011) Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer. J Hepatol 55:1339–1345
Amatangelo MD, Garipov A, Li H, Conejo-Garcia JR, Speicher DW, Zhang R (2013) Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition. Cell Cycle 12:2113–2119
Amodio N, Rossi M, Raimondi L, Pitari MR, Botta C, Tagliaferri P, Tassone P (2015) miR-29s: a family of epi-miRNAs with therapeutic implications in hematologic malignancies. Oncotarget 6:12837–12861
Asangani IA, Harms PW, Dodson L, Pandhi M, Kunju LP, Maher CA, Fullen DR, Johnson TM, Giordano TJ, Palanisamy N, Chinnaiyan AM (2012) Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget 3:1011–1025
Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, Iyer MK, Jing X, Wu YM, Cao X, Qin ZS, Wang S, Feng FY, Chinnaiyan AM (2014) Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510:278–282
Azmi AS, Beck FW, Bao B, Mohammad RM, Sarkar FH (2011) Aberrant epigenetic grooming of miRNAs in pancreatic cancer: a systems biology perspective. Epigenomics 3:747–759
Balaguer F, Link A, Lozano JJ, Cuatrecasas M, Nagasaka T, Boland CR, Goel A (2010) Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis. Cancer Res 70:6609–6618
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
Baylin SB, Jones PA (2016) Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol 8
Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21
Borno ST, Fischer A, Kerick M, Falth M, Laible M, Brase JC, Kuner R, Dahl A, Grimm C, Sayanjali B, Isau M, Rohr C, Wunderlich A, Timmermann B, Claus R, Plass C, Graefen M, Simon R, Demichelis F, Rubin MA, Sauter G, Schlomm T, Sultmann H, Lehrach H, Schweiger MR (2012) Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. Cancer Discov 2:1024–1035
Boulikas T (1989) DNA strand breaks alter histone ADP-ribosylation. Proc Natl Acad Sci U S A 86:3499–3503
Boumber Y, Issa JP (2011) Epigenetics in cancer: what’s the future? Oncol Williston Park 25:220–226. 228
Braconi C, Huang N, Patel T (2010) MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology 51:881–890
Bradner JE, Mak R, Tanguturi SK, Mazitschek R, Haggarty SJ, Ross K, Chang CY, Bosco J, West N, Morse E, Lin K, Shen JP, Kwiatkowski NP, Gheldof N, Dekker J, Deangelo DJ, Carr SA, Schreiber SL, Golub TR, Ebert BL (2010) Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci U S A 107:12617–12622
Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101:2999–3004
Cao P, Deng Z, Wan M, Huang W, Cramer SD, Xu J, Lei M, Sui G (2010) MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta. Mol Cancer 9:108
Cattaneo M, Pelosi E, Castelli G, Cerio AM, D’angio A, Porretti L, Rebulla P, Pavesi L, Russo G, Giordano A, Turri J, Cicconi L, Lo-Coco F, Testa U, Biunno I (2015) A miRNA Signature in Human Cord Blood Stem and Progenitor Cells as Potential Biomarker of Specific Acute Myeloid Leukemia Subtypes. J Cell Physiol 230:1770–1780
Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferre F, Bourque C, Burke CJ, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Ait-Si-Ali S, Garraway LA, Young RA, Zon LI (2011) The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471:513–517
Chaib H, Nebbioso A, Prebet T, Castellano R, Garbit S, Restouin A, Vey N, Altucci L, Collette Y (2012) Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1. Leukemia 26:662–674
Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I, Chaudhry MS, Rotolo A, Tough DF, Smithers NN, Bassil AK, Chapman TD, Harker NR, Barbash O, Tummino P, Al-Mahdi N, Haynes AC, Cutler L, Le B, Rahemtulla A, Roberts I, Kleijnen M, Witherington JJ, Parr NJ, Prinjha RK, Karadimitris A (2014) Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123:697–705
Chang X, Han J, Pang L, Zhao Y, Yang Y, Shen Z (2009) Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer 9:40
Chang KH, King ONF, Tumber A, Woon ECY, Heightman TD, Mcdonough MA, Schofield CJ, Rose NR (2011) Inhibition of histone demethylases by 4-carboxy-2,2′-bipyridyl compounds. ChemMedChem 6:759–764
Chang KW, Chu TH, Gong NR, Chiang WF, Yang CC, Liu CJ, Wu CH, Lin SC (2013) miR-370 modulates insulin receptor substrate-1 expression and inhibits the tumor phenotypes of oral carcinoma. Oral Dis 19:611–619
Chen Y, Luo J, Tian R, Sun H, Zou S (2011) miR-373 negatively regulates methyl-CpG-binding domain protein 2 (MBD2) in hilar cholangiocarcinoma. Dig Dis Sci 56:1693–1701
Chen Z, Liu S, Tian L, Wu M, Ai F, Tang W, Zhao L, Ding J, Zhang L, Tang A (2015) miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1. Oncotarget 6:38139–38150
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840
Christophorou MA, Castelo-Branco G, Halley-Stott RP, Oliveira CS, Loos R, Radzisheuskaya A, Mowen KA, Bertone P, Silva JC, Zernicka-Goetz M, Nielsen ML, Gurdon JB, Kouzarides T (2014) Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 507:104–108
Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I (2011) TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 9:193–204
Cohen EE, Zhu H, Lingen MW, Martin LE, Kuo WL, Choi EA, Kocherginsky M, Parker JS, Chung CH, Rosner MR (2009) A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. Cancer Res 69:65–74
Cortez CC, Jones PA (2008) Chromatin, cancer and drug therapies. Mutat Res 647:44–51
Creagan ET, Schaid DJ, Hartmann LC, Loprinzi CL (1993) A phase II study of 5,6-dihydro-5-azacytidine hydrochloride in disseminated malignant melanoma. Am J Clin Oncol 16:243–244
Cress WD, Seto E (2000) Histone deacetylases, transcriptional control, and cancer. J Cell Physiol 184:1–16
Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, Jin L, Kuntz KW, Chesworth R, Moyer MP, Bernt KM, Tseng JC, Kung AL, Armstrong SA, Copeland RA, Richon VM, Pollock RM (2011) Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20:53–65
Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S, Liu CG, Volinia S, Croce CM, Schmittgen TD, Ghoshal K, Jacob ST (2008) Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68:5049–5058
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301
Dillhoff M, Liu J, Frankel W, Croce C, Bloomston M (2008) MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg 12:2171–2176
Dohi O, Yasui K, Gen Y, Takada H, Endo M, Tsuji K, Konishi C, Yamada N, Mitsuyoshi H, Yagi N, Naito Y, Tanaka S, Arii S, Yoshikawa T (2013) Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma. Int J Oncol 42:411–418
Duursma AM, Kedde M, Schrier M, LE Sage C, Agami R (2008) miR-148 targets human DNMT3b protein coding region. RNA 14:872–877
Ehrbrecht A, Muller U, Wolter M, Hoischen A, Koch A, Radlwimmer B, Actor B, Mincheva A, Pietsch T, Lichter P, Reifenberger G, Weber RG (2006) Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol 208:554–563
Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, Cervantes F, Oscier D, Boultwood J, Grand FH, Cross NC (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42:722–726
Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6:259–269
Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–569
Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison CD, Chan KK, Marcucci G, Calin GA, Huebner K, Croce CM (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104:15805–15810
Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4:143–153
Fenaux P, Ades L (2009) Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. Leuk Res 33(Suppl 2):S7–S11
Filippakopoulos P, Knapp S (2012) The bromodomain interaction module. FEBS Lett 586:2692–2704
Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S (2012) Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149:214–231
Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, Ustun C, Rao R, Fernandez P, Chen J, Balusu R, Koul S, Atadja P, Marquez VE, Bhalla KN (2009) Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114:2733–2743
Formosa A, Lena AM, Markert EK, Cortelli S, Miano R, Mauriello A, Croce N, Vandesompele J, Mestdagh P, Finazzi-Agro E, Levine AJ, Melino G, Bernardini S, Candi E (2013) DNA methylation silences miR-132 in prostate cancer. Oncogene 32:127–134
Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033
French CA (2010) Demystified molecular pathology of NUT midline carcinomas. J Clin Pathol 63:492–496
Friedman JM, Jones PA (2009) MicroRNAs: critical mediators of differentiation, development and disease. Swiss Med Wkly 139:466–472
Garzon R, Calin GA, Croce CM (2009a) MicroRNAs in Cancer. Annu Rev Med 60:167–179
Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, Andreeff M, Croce CM (2009b) MicroRNA 29b functions in acute myeloid leukemia. Blood 114:5331–5341
Ghoshal K, Datta J, Majumder S, Bai S, Kutay H, Motiwala T, Jacob ST (2005) 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 25:4727–4741
Glozak MA, Seto E (2007) Histone deacetylases and cancer. Oncogene 26:5420–5432
Gong AY, Eischeid AN, Xiao J, Zhao J, Chen D, Wang ZY, Young CY, Chen XM (2012) miR-17-5p targets the p300/CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells. BMC Cancer 12:492
Greenwald RJ, Tumang JR, Sinha A, Currier N, Cardiff RD, Rothstein TL, Faller DV, Denis GV (2004) E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia. Blood 103:1475–1484
Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature 389:349–352
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, Field HI, Neal DE, Yamaue H, Ponder BA, Nakamura Y, Hamamoto R (2011) Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer 128:574–586
Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV, Boesen T, Labelle M, Gerlach LO, Birk P, Helin K (2014) Inhibition of demethylases by GSK-J1/J4. Nature 514:E1–E2
Helin K, Dhanak D (2013) Chromatin proteins and modifications as drug targets. Nature 502:480–488
Herold JM, Ingerman LA, Gao C, Frye SV (2011) Drug discovery toward antagonists of methyl-lysine binding proteins. Curr Chem Genomics 5:51–61
Hirota T, Lipp JJ, Toh BH, Peters JM (2005) Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438:1176–1180
Hossain MB, Vahter M, Concha G, Broberg K (2012) Low-level environmental cadmium exposure is associated with DNA hypomethylation in Argentinean women. Environ Health Perspect 120:879–884
Huang H, Lin S, Garcia BA, Zhao Y (2015) Quantitative proteomic analysis of histone modifications. Chem Rev 115:2376–2418
Hulf T, Sibbritt T, Wiklund ED, Bert S, Strbenac D, Statham AL, Robinson MD, Clark SJ (2011) Discovery pipeline for epigenetically deregulated miRNAs in cancer: integration of primary miRNA transcription. BMC Genomics 12:54
Humphreys KJ, Cobiac L, le Leu RK, van der Hoek MB, Michael MZ (2013) Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster. Mol Carcinog 52:459–474
Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N, Rowan R, Amaral S, Curley D, Williams IR, Akashi K, Gilliland DG (2004) MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6:587–596
Hwang JJ, Kim YS, Kim T, Kim MJ, Jeong IG, Lee JH, Choi J, Jang S, Ro S, Kim CS (2012) A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL. Invest New Drugs 30:1434–1442
Ismail IH, Mcdonald D, Strickfaden H, Xu Z, Hendzel MJ (2013) A small molecule inhibitor of polycomb repressive complex 1 inhibits ubiquitin signaling at DNA double-strand breaks. J Biol Chem 288:26944–26954
Iyer NG, Ozdag H, Caldas C (2004) p300/CBP and cancer. Oncogene 23:4225–4231
James LI, Barsyte-Lovejoy D, Zhong N, Krichevsky L, Korboukh VK, Herold JM, Macnevin CJ, Norris JL, Sagum CA, Tempel W, Marcon E, Guo H, Gao C, Huang XP, Duan S, Emili A, Greenblatt JF, Kireev DB, Jin J, Janzen WP, Brown PJ, Bedford MT, Arrowsmith CH, Frye SV (2013) Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat Chem Biol 9:184–191
Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, Dipersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803
Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O’brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP (2007) Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109:52–57
Kim J, Bretz CL, Lee S (2015) Epigenetic instability of imprinted genes in human cancers. Nucleic Acids Res 43:10689–10699
Kippler M, Hossain MB, Lindh C, Moore SE, Kabir I, Vahter M, Broberg K (2012) Early life low-level cadmium exposure is positively associated with increased oxidative stress. Environ Res 112:164–170
Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8:890–896
Kooistra SM, Helin K (2012) Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol 13:297–311
Lautz TB, Naiditch JA, Clark S, Chu F, Madonna MB (2012) Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma. J Pediatr Surg 47:1267–1271
Lavelle D, Saunthararajah Y, Vaitkus K, Singh M, Banzon V, Phiasivongsva P, Redkar S, Kanekal S, Bearss D, Shi C, Inloes R, Desimone J (2010) S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis). J Transl Med 8:92
Lei Q, Liu X, Fu H, Sun Y, Wang L, Xu G, Wang W, Yu Z, Liu C, Li P, Feng J, Li G, Wu M (2016) miR-101 reverses hypomethylation of the PRDM16 promoter to disrupt mitochondrial function in astrocytoma cells. Oncotarget 7:5007–5022
Li Q, Zou C, Han Z, Xiao H, Wei H, Wang W, Zhang L, Zhang X, Tang Q, Zhang C, Tao J, Wang X, Gao X (2013) MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. Cancer Lett 335:168–174
Liu G, Bollig-Fischer A, Kreike B, van de Vijver MJ, Abrams J, Ethier SP, Yang ZQ (2009) Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28:4491–4500
Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H, Knyazev P, Diebold J, Hermeking H (2008) Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 7:2591–2600
Loidl P (1994) Histone acetylation: facts and questions. Chromosoma 103:441–449
Lu Z, Tian Y, Salwen HR, Chlenski A, Godley LA, Raj JU, Yang Q (2013) Histone-lysine methyltransferase EHMT2 is involved in proliferation, apoptosis, cell invasion, and DNA methylation of human neuroblastoma cells. Anticancer Drugs 24:484–493
Lucas DM, Alinari L, West DA, Davis ME, Edwards RB, Johnson AJ, Blum KA, Hofmeister CC, Freitas MA, Parthun MR, Wang D, Lehman A, Zhang X, Jarjoura D, Kulp SK, Croce CM, Grever MR, Chen CS, Baiocchi RA, Byrd JC (2010) The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo. PLoS One 5:e10941
Majid S, Dar AA, Saini S, Shahryari V, Arora S, Zaman MS, Chang I, Yamamura S, Tanaka Y, Chiyomaru T, Deng G, Dahiya R (2013) miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways. Clin Cancer Res 19:73–84
Mandl-Weber S, Meinel FG, Jankowsky R, Oduncu F, Schmidmaier R, Baumann P (2010) The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br J Haematol 149:518–528
Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658
Messner S, Altmeyer M, Zhao H, Pozivil A, Roschitzki B, Gehrig P, Rutishauser D, Huang D, Caflisch A, Hottiger MO (2010) PARP1 ADP-ribosylates lysine residues of the core histone tails. Nucleic Acids Res 38:6350–6362
Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51
Moazzen S, Dolatkhah R, Tabrizi JS, Shaarbafi J, Alizadeh BZ, de Bock GH, Dastgiri S (2017) Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis. Clin Nutr.
Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 42:181–185
Mosammaparast N, Shi Y (2010) Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem 79:155–179
Nair SS, Kumar R (2012) Chromatin remodeling in cancer: a gateway to regulate gene transcription. Mol Oncol 6:611–619
Nguyen AT, Taranova O, He J, Zhang Y (2011) DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood 117:6912–6922
Ning B, Li W, Zhao W, Wang R (2016) Targeting epigenetic regulations in cancer. Acta Biochim Biophys Sin (Shanghai) 48:97–109
Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, Hirata H, Giardina C, Dahiya R (2009) miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 28:1714–1724
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257
Oki Y, Kantarjian HM, Gharibyan V, Jones D, O’brien S, Verstovsek S, Cortes J, Morris GM, Garcia-Manero G, Issa JP (2007) Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer 109:899–906
Pasquinelli AE, Hunter S, Bracht J (2005) MicroRNAs: a developing story. Curr Opin Genet Dev 15:200–205
Rauhala HE, Jalava SE, Isotalo J, Bracken H, Lehmusvaara S, Tammela TL, Oja H, Visakorpi T (2010) miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer. Int J Cancer 127:1363–1372
Reichard JF, Puga A (2010) Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics 2:87–104
Rideout WM 3rd, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249:1288–1290
Rodriguez-Paredes M, Martinez De Paz A, Simo-Riudalbas L, Sayols S, Moutinho C, Moran S, Villanueva A, Vazquez-Cedeira M, Lazo PA, Carneiro F, Moura CS, Vieira J, Teixeira MR, Esteller M (2014) Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene 33:2807–2813
Ruthenburg AJ, Li H, Patel DJ, Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8:983–994
Saint-Martin C, Leroy G, Delhommeau F, Panelatti G, Dupont S, James C, Plo I, Bordessoule D, Chomienne C, Delannoy A, Devidas A, Gardembas-Pain M, Isnard F, Plumelle Y, Bernard O, Vainchenker W, Najman A, Bellanne-Chantelot C (2009) Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms. Blood 114:1628–1632
Saito Y, Jones PA (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222
Saito Y, Friedman JM, Chihara Y, Egger G, Chuang JC, Liang G (2009) Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochem Biophys Res Commun 379:726–731
Sakabe K, Wang Z, Hart GW (2010) Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci U S A 107:19915–19920
Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG, Keating MJ (2012) Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood 119:1162–1172
Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci U S A 103:1412–1417
Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K, Klein HU, Popescu AC, Burnett A, Mills K, Casero RA Jr, Marton L, Woster P, Minden MD, Dugas M, Wang JC, Dick JE, Muller-Tidow C, Petrie K, Zelent A (2012) Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 18:605–611
Schnekenburger M, Diederich M (2012) Epigenetics Offer New Horizons for Colorectal Cancer Prevention. Curr Colorectal Cancer Rep 8:66–81
Seto E, Yoshida M (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol 6:a018713
Shabbir M, Stuart R (2010) Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside. Expert Opin Investig Drugs 19:427–436
Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, Berry D, Ahmed S, Zhu W, Pierce S, Kondo Y, Oki Y, Jelinek J, Saba H, Estey E, Issa JP (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28:605–613
Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953
Sproul D, Meehan RR (2013) Genomic insights into cancer-associated aberrant CpG island hypermethylation. Brief Funct Genomics 12:174–190
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q (2007) Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21:1050–1063
Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14:1025–1040
Toyokawa G, Cho HS, Masuda K, Yamane Y, Yoshimatsu M, Hayami S, Takawa M, Iwai Y, Daigo Y, Tsuchiya E, Tsunoda T, Field HI, Kelly JD, Neal DE, Maehara Y, Ponder BA, Nakamura Y, Hamamoto R (2011) Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the Wnt pathway. Neoplasia 13:887–898
Uribe-Lewis S, Woodfine K, Stojic L, Murrell A (2011) Molecular mechanisms of genomic imprinting and clinical implications for cancer. Expert Rev Mol Med 13:e2
Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322:1695–1699
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J (2011) A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 7:566–574
Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, Estrov Z, Fridman JS, Bradley EC, Erickson-Viitanen S, Vaddi K, Levy R, Tefferi A (2010) Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363:1117–1127
Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, Mcdonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306:279–283
Wang J, Iwasaki H, Krivtsov A, Febbo PG, Thorner AR, Ernst P, Anastasiadou E, Kutok JL, Kogan SC, Zinkel SS, Fisher JK, Hess JL, Golub TR, Armstrong SA, Akashi K, Korsmeyer SJ (2005) Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J 24:368–381
Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, Joshi A, Balusu R, Koul S, Chen J, Savoie A, Ustun C, Jillella AP, Atadja P, Levine RL, Bhalla KN (2009) Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 114:5024–5033
Wang Z, Udeshi ND, Slawson C, Compton PD, Sakabe K, Cheung WD, Shabanowitz J, Hunt DF, Hart GW (2010) Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci Signal 3:ra2
Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R, Liu Y, Ward D, Quan J, Ye T, Zhang H (2011) Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 71:7238–7249
Wang Y, Toh HC, Chow P, Chung AY, Meyers DJ, Cole PA, Ooi LL, Lee CG (2012) MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms. FASEB J 26:3032–3041
Wang LH, Huang J, Wu CR, Huang LY, Cui J, Xing ZZ, Zhao CY (2018) Downregulation of miR29b targets DNMT3b to suppress cellular apoptosis and enhance proliferation in pancreatic cancer. Mol Med Rep 17:2113–2120
Weintraub H, Groudine M (1976) Chromosomal subunits in active genes have an altered conformation. Science 193:848–856
Winquist E, Knox J, Ayoub JP, Wood L, Wainman N, Reid GK, Pearce L, Shah A, Eisenhauer E (2006) Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study. Invest New Drugs 24:159–167
Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE (2015) Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–1381
Wotschofsky Z, Busch J, Jung M, Kempkensteffen C, Weikert S, Schaser KD, Melcher I, Kilic E, Miller K, Kristiansen G, Erbersdobler A, Jung K (2013) Diagnostic and prognostic potential of differentially expressed miRNAs between metastatic and non-metastatic renal cell carcinoma at the time of nephrectomy. Clin Chim Acta 416:5–10
Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25:2436–2452
Wu H, D’alessio AC, Ito S, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y (2011) Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev 25:679–684
Wu T, Qu L, He G, Tian L, Li L, Zhou H, Jin Q, Ren J, Wang Y, Wang J, Kan X, Liu M, Shen J, Guo M, Sun Y (2016) Regulation of laryngeal squamous cell cancer progression by the lncRNA H19/miR-148a-3p/DNMT1 axis. Oncotarget 7:11553–11566
Xu X, Chen Z, Zhao X, Wang J, Ding D, Wang Z, Tan F, Tan X, Zhou F, Sun J, Sun N, Gao Y, Shao K, Li N, Qiu B, He J (2012) MicroRNA-25 promotes cell migration and invasion in esophageal squamous cell carcinoma. Biochem Biophys Res Commun 421:640–645
Yang Z, Yik JH, Chen R, He N, Jang MK, Ozato K, Zhou Q (2005) Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 19:535–545
Yang X, Feng M, Jiang X, Wu Z, Li Z, Aau M, Yu Q (2009) miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes Dev 23:2388–2393
Yang S, Li Y, Gao J, Zhang T, Li S, Luo A, Chen H, Ding F, Wang X, Liu Z (2013) MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene 32:4294–4303
Yao YL, Ma J, Wang P, Xue YX, Li Z, Zhao LN, Li ZQ, Feng TD, Liu YH (2015) miR-101 acts as a tumor suppressor by targeting Kruppel-like factor 6 in glioblastoma stem cells. CNS Neurosci Ther 21:40–51
Yuan Y, Wang Q, Paulk J, Kubicek S, Kemp MM, Adams DJ, Shamji AF, Wagner BK, Schreiber SL (2012) A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol 7:1152–1157
Zaman MS, Chen Y, Deng G, Shahryari V, Suh SO, Saini S, Majid S, Liu J, Khatri G, Tanaka Y, Dahiya R (2010) The functional significance of microRNA-145 in prostate cancer. Br J Cancer 103:256–264
Zhang P, Huang A, Ferruzzi J, Mecham RP, Starcher BC, Tellides G, Humphrey JD, Giordano FJ, Niklason LE, Sessa WC (2012) Inhibition of microRNA-29 enhances elastin levels in cells haploinsufficient for elastin and in bioengineered vessels--brief report. Arterioscler Thromb Vasc Biol 32:756–759
Zhao Y, Garcia BA (2015) Comprehensive Catalog of Currently Documented Histone Modifications. Cold Spring Harb Perspect Biol 7:a025064
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Mansuri, M.S., Mehrotra, S. (2019). Emerging Epigenetic Targets and Their Implications in Cancer Therapy. In: Bose, K., Chaudhari, P. (eds) Unravelling Cancer Signaling Pathways: A Multidisciplinary Approach. Springer, Singapore. https://doi.org/10.1007/978-981-32-9816-3_7
Download citation
DOI: https://doi.org/10.1007/978-981-32-9816-3_7
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-32-9815-6
Online ISBN: 978-981-32-9816-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)