Pharmacological treatment and exposure to xenobiotics can cause substantial changes in epigenetic signatures. The majority of these epigenetic changes, caused by the compounds in question, occur downstream of transcriptional activation mechanisms, whereby the epigenetic alterations can create a transcriptional memory and stably modulate cell function. The increasing understanding of epigenetic mechanisms and their importance in disease has prompted the development of therapeutic interventions that target epigenetic modulatory mechanisms, particularly in oncology where inhibitors of epigenetic-modifying proteins (epidrugs) have been successfully used in treatment, mostly in combination with standard-of-care chemotherapy, either provoking direct cytotoxicity or inhibiting resistance to anticancer drugs. In addition, emerging methods for detecting epigenetically modified DNA in bodily fluids may provide information about tumor phenotype or drug treatment success. However, it is important to note that many technical pitfalls, such as the nondeconvolution of methylcytosine and hydroxymethylcytosine, compromise epigenetic analyses and the interpretation of results. In this review, we provide an update on the field, with an emphasis on the novel therapeutic opportunities made possible by epidrugs.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Spear BB, Heath-Chiozzi M, Huff J. 1.  2001. Clinical application of pharmacogenetics. Trends Mol. Med. 7:201–4 [Google Scholar]
  2. Lauschke VM, Ingelman-Sundberg M. 2.  2016. The importance of patient-specific factors for hepatic drug response and toxicity. Int. J. Mol. Sci. 17:714 [Google Scholar]
  3. Feil R, Fraga MF. 3.  2012. Epigenetics and the environment: emerging patterns and implications. Nat. Rev. Genet. 13:97–109 [Google Scholar]
  4. Bowers EC, McCullough SD. 4.  2016. Linking the epigenome with exposure effects and susceptibility: the epigenetic seed and soil model. Toxicol. Sci. 155:302–14 [Google Scholar]
  5. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ. 5.  et al. 2008. Persistent epigenetic differences associated with prenatal exposure to famine in humans. PNAS 105:17046–49 [Google Scholar]
  6. Tan Q, Heijmans BT, Hjelmborg JvB, Soerensen M, Christensen K, Christiansen L. 6.  2016. Epigenetic drift in the aging genome: a ten-year follow-up in an elderly twin cohort. Int. J. Epidemiol. 45:1146–58 [Google Scholar]
  7. Allis CD, Jenuwein T. 7.  2016. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17:487–500 [Google Scholar]
  8. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y. 8.  et al. 2012. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–80 [Google Scholar]
  9. Le Dily F, Baù D, Pohl A, Vicent GP, Serra F. 9.  et al. 2014. Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation. Genes Dev 28:2151–62 [Google Scholar]
  10. Pombo A, Dillon N. 10.  2015. Three-dimensional genome architecture: players and mechanisms. Nat. Rev. Mol. Cell Biol. 16:245–57 [Google Scholar]
  11. Ordu O, Lusser A, Dekker NH. 11.  2016. Recent insights from in vitro single-molecule studies into nucleosome structure and dynamics. Biophys. Rev. 8:Suppl. 133–49 [Google Scholar]
  12. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ. 12.  et al. 2006. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–26 [Google Scholar]
  13. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H. 13.  et al. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–35 [Google Scholar]
  14. Kriaucionis S, Heintz N. 14.  2009. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–30 [Google Scholar]
  15. Bachman M, Uribe-Lewis S, Yang X, Williams M, Murrell A, Balasubramanian S. 15.  2014. 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat. Chem. 6:1049–55 [Google Scholar]
  16. Bachman M, Uribe-Lewis S, Yang X, Burgess HE, Iurlaro M. 16.  et al. 2015. 5-Formylcytosine can be a stable DNA modification in mammals. Nat. Chem. Biol. 11:555–57 [Google Scholar]
  17. Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PWTC. 17.  et al. 2013. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152:1146–59 [Google Scholar]
  18. Pfaffeneder T, Spada F, Wagner M, Brandmayr C, Laube SK. 18.  et al. 2014. Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat. Chem. Biol. 10:574–81 [Google Scholar]
  19. Ivanov M, Kals M, Kacevska M, Barragan I, Kasuga K. 19.  et al. 2013. Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function. Genome Biol 14:R83 [Google Scholar]
  20. Globisch D, Münzel M, Müller M, Michalakis S, Wagner M. 20.  et al. 2010. Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLOS ONE 5:e15367 [Google Scholar]
  21. Kraus TFJ, Globisch D, Wagner M, Eigenbrod S, Widmann D. 21.  et al. 2012. Low values of 5-hydroxymethylcytosine (5hmC), the “sixth base,” are associated with anaplasia in human brain tumors. Int. J. Cancer 131:1577–90 [Google Scholar]
  22. Ivanov M, Kals M, Lauschke VM, Barragan I, Ewels P. 22.  et al. 2016. Single base resolution analysis of 5-hydroxymethylcytosine in 188 human genes: implications for hepatic gene expression. Nucleic Acids Res 44:6756–69 [Google Scholar]
  23. Yu M, Hon GC, Szulwach KE, Song C-X, Jin P. 23.  et al. 2012. Tet-assisted bisulfite sequencing of 5-hydroxymethylcytosine. Nat. Protoc. 7:2159–70 [Google Scholar]
  24. Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F. 24.  et al. 2012. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 336:934–37 [Google Scholar]
  25. Kawasaki Y, Kuroda Y, Suetake I, Tajima S, Ishino F, Kohda T. 25.  2016. A novel method for the simultaneous identification of methylcytosine and hydroxymethylcytosine at a single base resolution. Nucleic Acids Res 45:e24 [Google Scholar]
  26. Ramsey LB, Bruun GH, Yang W, Trevino LR, Vattathil S. 26.  et al. 2012. Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res 22:1–8 [Google Scholar]
  27. Lempiäinen H, Müller A, Brasa S, Teo S-S, Roloff T-C. 27.  et al. 2011. Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice. PLOS ONE 6:e18216–14 [Google Scholar]
  28. Thomson JP, Hunter JM, Lempiainen H, Müller A, Terranova R. 28.  et al. 2013. Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver. Nucleic Acids Res 41:5639–54 [Google Scholar]
  29. Englert NA, Luo G, Goldstein JA, Surapureddi S. 29.  2015. Epigenetic modification of histone 3 lysine 27: mediator subunit MED25 is required for the dissociation of Polycomb repressive complex 2 from the promoter of cytochrome P450 2C9. J. Biol. Chem. 290:2264–78 [Google Scholar]
  30. Tang X, Ge L, Chen Z, Kong S, Liu W. 30.  et al. 2016. Methylation of the constitutive androstane receptor is involved in the suppression of CYP2C19 in hepatitis B virus–associated hepatocellular carcinoma. Drug Metab. Dispos. 44:1643–52 [Google Scholar]
  31. Habano W, Kawamura K, Iizuka N, Terashima J, Sugai T, Ozawa S. 31.  2015. Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes. Clin. Epigenetics 7:105 [Google Scholar]
  32. Westlind A, Löfberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M. 32.  1999. Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region. Biochem. Biophys. Res. Commun. 259:201–5 [Google Scholar]
  33. Zhou Y, Ingelman-Sundberg M, Lauschke VM. 33.  2017. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin. Pharmacol. Ther. 102:688–700 [Google Scholar]
  34. Xie Y, Ke S, Ouyang N, He J, Xie W. 34.  et al. 2009. Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1. J. Biol. Chem. 284:9199–205 [Google Scholar]
  35. Kacevska M, Ivanov M, Wyss A, Kasela S, Milani L. 35.  et al. 2012. DNA methylation dynamics in the hepatic CYP3A4 gene promoter. Biochimie 94:2338–44 [Google Scholar]
  36. Fisel P, Schaeffeler E, Schwab M. 36.  2016. DNA methylation of ADME genes. Clin. Pharmacol. Ther. 99:512–27 [Google Scholar]
  37. Ivanov M, Barragan I, Ingelman-Sundberg M. 37.  2014. Epigenetic mechanisms of importance for drug treatment. Trends Pharmacol. Sci. 35:384–96 [Google Scholar]
  38. Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. 38.  2004. Role of aryl hydrocarbon receptor–mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J. Biol. Chem. 279:23847–50 [Google Scholar]
  39. Beedanagari SR, Taylor RT, Bui P, Wang F, Nickerson DW, Hankinson O. 39.  2010. Role of epigenetic mechanisms in differential regulation of the dioxin-inducible human CYP1A1 and CYP1B1 genes. Mol. Pharmacol. 78:608–16 [Google Scholar]
  40. Yu K, Shi Y-F, Yang K-Y, Zhuang Y, Zhu R-H. 40.  et al. 2011. Decreased topoisomerase IIα expression and altered histone and regulatory factors of topoisomerase IIα promoter in patients with chronic benzene poisoning. Toxicol. Lett. 203:111–17 [Google Scholar]
  41. Zhang Y-J, Ahsan H, Chen Y, Lunn RM, Wang L-Y. 41.  et al. 2002. High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma. Mol. Carcinog. 35:85–92 [Google Scholar]
  42. Hernandez-Vargas H, Castelino J, Silver MJ, Dominguez-Salas P, Cros M-P. 42.  et al. 2015. Exposure to aflatoxin B1 in utero is associated with DNA methylation in white blood cells of infants in The Gambia. Int. J. Epidemiol. 44:1238–48 [Google Scholar]
  43. Shenker NS, Polidoro S, van Veldhoven K, Sacerdote C, Ricceri F. 43.  et al. 2013. Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum. Mol. Genet. 22:843–51 [Google Scholar]
  44. Kundakovic M, Gudsnuk K, Herbstman JB, Tang D, Perera FP, Champagne FA. 44.  2015. DNA methylation of BDNF as a biomarker of early-life adversity. PNAS 112:6807–13 [Google Scholar]
  45. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. 45.  2013. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLOS ONE 8:e55387 [Google Scholar]
  46. Anway MD, Leathers C, Skinner MK. 46.  2006. Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147:5515–23 [Google Scholar]
  47. Guerrero-Bosagna C, Covert TR, Haque MM, Settles M, Nilsson EE. 47.  et al. 2012. Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers. Reprod. Toxicol 34:694–707 [Google Scholar]
  48. Portela A, Esteller M. 48.  2010. Epigenetic modifications and human disease. Nat. Biotechnol. 28:1057–68 [Google Scholar]
  49. Ehrlich M. 49.  2009. DNA hypomethylation in cancer cells. Epigenomics 1:239–59 [Google Scholar]
  50. Feinberg AP, Koldobskiy MA, Göndör A. 50.  2016. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17:284–99 [Google Scholar]
  51. Wouters BJ, Delwel R. 51.  2016. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 127:42–52 [Google Scholar]
  52. Ceccacci E, Minucci S. 52.  2016. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia. Br. J. Cancer 114:605–11 [Google Scholar]
  53. Dawson MA, Kouzarides T. 53.  2012. Cancer epigenetics: from mechanism to therapy. Cell 150:12–27 [Google Scholar]
  54. Santi DV, Norment A, Garrett CE. 54.  1984. Covalent bond formation between a DNA–cytosine methyltransferase and DNA containing 5-azacytosine. PNAS 81:6993–97 [Google Scholar]
  55. Lyko F, Brown R. 55.  2005. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J. Natl. Cancer Inst. 97:1498–506 [Google Scholar]
  56. Plummer R, Vidal L, Griffin M, Lesley M, de Bono J. 56.  et al. 2009. Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. Clin. Cancer Res. 15:3177–83 [Google Scholar]
  57. Dueñas-Gonzalez A, Coronel J, Cetina L, González-Fierro A, Chavez-Blanco A, Taja-Chayeb L. 57.  2014. Hydralazine–valproate: a repositioned drug combination for the epigenetic therapy of cancer. Expert Opin. Drug Metab. Toxicol. 10:1433–44 [Google Scholar]
  58. Xu WS, Parmigiani RB, Marks PA. 58.  2007. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–52 [Google Scholar]
  59. Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A. 59.  et al. 2010. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer: preliminary results. Med. Oncol. 28:540–46 [Google Scholar]
  60. Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP. 60.  et al. 2005. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 20:212–17 [Google Scholar]
  61. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M. 61.  et al. 2011. Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer. Cancer Discov 1:598–607 [Google Scholar]
  62. Voso MT, Santini V, Finelli C, Musto P, Pogliani E. 62.  et al. 2009. Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin. Cancer Res. 15:5002–7 [Google Scholar]
  63. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. 63.  2003. EZH2 is downstream of the pRB–E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22:5323–35 [Google Scholar]
  64. Kim KH, Roberts CWM. 64.  2016. Targeting EZH2 in cancer. Nat. Med. 22:128–34 [Google Scholar]
  65. Gibaja V, Shen F, Harari J, Korn J, Ruddy D. 65.  et al. 2016. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene 35:558–66 [Google Scholar]
  66. Masliah-Planchon J, Bièche I, Guinebretière J-M, Bourdeaut F, Delattre O. 66.  2015. SWI/SNF chromatin remodeling and human malignancies. Annu. Rev. Pathol. 10:145–71 [Google Scholar]
  67. Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A. 67.  et al. 2015. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21:1491–96 [Google Scholar]
  68. Nguyen AT, Taranova O, He J, Zhang Y. 68.  2011. DOT1L, the H3K79 methyltransferase, is required for MLL–AF9–mediated leukemogenesis. Blood 117:6912–22 [Google Scholar]
  69. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L. 69.  et al. 2013. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122:1017–25 [Google Scholar]
  70. Shukla N, Wetmore C, O'Brien MM, Silverman LB, Brown P. 70.  et al. 2016. Final report of phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in children with relapsed or refractory MLL-r acute leukemia. Presented at Annu. Meet. Expo. Am. Soc. Hematol., 58th, San Diego. https://ash.confex.com/ash/2016/webprogram/Paper98350.html
  71. Schenk T, Chen WC, Göllner S, Howell L, Jin L. 71.  et al. 2012. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18:605–11 [Google Scholar]
  72. Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SGT. 72.  et al. 2014. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 28:2155–64 [Google Scholar]
  73. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M. 73.  et al. 2009. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J. Clin. Oncol. 28:56–62 [Google Scholar]
  74. Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL. 74.  et al. 2010. Phase 1b–2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer 117:1661–69 [Google Scholar]
  75. Wang JS-Z, Gootjes EC, Uram JN, Zahurak M, El-Khoueiry AB. 75.  et al. 2015. A phase I study of investigational agent SGI-110 combined with irinotecan in previously treated metastatic colorectal cancer patients. J. Clin. Oncol. 33:Suppl. 3TPS797 [Google Scholar]
  76. San-Miguel JF, Hungria VTM, Yoon S-S, Beksac M, Dimopoulos MA. 76.  et al. 2014. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195–206 [Google Scholar]
  77. Cole SPC. 77.  2014. Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annu. Rev. Pharmacol. Toxicol. 54:95–117 [Google Scholar]
  78. Brock A, Chang H, Huang S. 78.  2009. Non-genetic heterogeneity—a mutation-independent driving force for the somatic evolution of tumours. Nat. Rev. Genet. 10:336–42 [Google Scholar]
  79. Austin Doyle L, Ross DD. 79.  2003. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22:7340–58 [Google Scholar]
  80. Greaves W, Xiao L, Sanchez-Espiridion B, Kunkalla K, Dave KS. 80.  et al. 2012. Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols. J. Hematol. Oncol. 5:47 [Google Scholar]
  81. Eadie LN, Dang P, Saunders VA, Yeung DT, Osborn MP. 81.  et al. 2016. The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. Leukemia 31:75–82 [Google Scholar]
  82. Tada Y, Wada M, Kuroiwa K, Kinugawa N, Harada T. 82.  et al. 2000. MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment. Clin. Cancer Res. 6:4618–27 [Google Scholar]
  83. Bram EE, Stark M, Raz S, Assaraf YG. 83.  2009. Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance. Neoplasia 11:1359–70 [Google Scholar]
  84. Liu Y, Zheng X, Yu Q, Wang H, Tan F. 84.  et al. 2016. Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin. Sci. Transl. Med. 8:348 [Google Scholar]
  85. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N. 85.  et al. 2005. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352:997–1003 [Google Scholar]
  86. Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. 86.  2000. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 60:6039–44 [Google Scholar]
  87. Chang X, Monitto CL, Demokan S, Kim MS, Chang SS. 87.  et al. 2010. Identification of hypermethylated genes associated with cisplatin resistance in human cancers. Cancer Res 70:2870–79 [Google Scholar]
  88. Balko JM, Cook RS, Vaught DB, Kuba MG, Miller TW. 88.  et al. 2012. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat. Med. 18:1052–59 [Google Scholar]
  89. Waha A, Felsberg J, Hartmann W, von dem Knesebeck A, Mikeska T. 89.  et al. 2010. Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer Res 70:1689–99 [Google Scholar]
  90. Watanabe Y, Ueda H, Etoh T, Koike E, Fujinami N. 90.  et al. 2007. A change in promoter methylation of hMLH1 is a cause of acquired resistance to platinum-based chemotherapy in epithelial ovarian cancer. Anticancer Res 27:1449–52 [Google Scholar]
  91. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F. 91.  et al. 2010. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69–80 [Google Scholar]
  92. El-Khoury V, Breuzard G, Fourré N, Dufer J. 92.  2007. The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model. Br. J. Cancer 97:562–73 [Google Scholar]
  93. Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG. 93.  et al. 2014. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46:364–70 [Google Scholar]
  94. Brown R, Curry E, Magnani L, Wilhelm-Benartzi CS, Borley J. 94.  2014. Poised epigenetic states and acquired drug resistance in cancer. Nat. Rev. Cancer 14:747–53 [Google Scholar]
  95. Smolen JS, Aletaha D. 95.  2015. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Neurosci. 11:276–89 [Google Scholar]
  96. Plant D, Webster A, Nair N, Oliver J, Smith SL. 96.  et al. 2016. Differential methylation as a biomarker of response to etanercept in patients with rheumatoid arthritis. Arthritis Rheumatol 68:1353–60 [Google Scholar]
  97. Grabiec AM, Krausz S, de Jager W, Burakowski T, Groot D. 97.  et al. 2010. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J. Immunol. 184:2718–28 [Google Scholar]
  98. Joosten LAB, Leoni F, Meghji S, Mascagni P. 98.  2011. Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol. Med. 17:391–96 [Google Scholar]
  99. Vojinovic J, Damjanov N. 99.  2011. HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. Mol. Med. 17:397–403 [Google Scholar]
  100. Regna NL, Chafin CB, Hammond SE, Puthiyaveetil AG, Caudell DL, Reilly CM. 100.  2014. Class I and II histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo. Clin. Immunol. 151:29–42 [Google Scholar]
  101. Carta S, Tassi S, Semino C, Fossati G, Mascagni P. 101.  et al. 2006. Histone deacetylase inhibitors prevent exocytosis of interleukin-1β-containing secretory lysosomes: role of microtubules. Blood 108:1618–26 [Google Scholar]
  102. Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V. 102.  et al. 2016. The genetic architecture of type 2 diabetes. Nature 536:41–47 [Google Scholar]
  103. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL. 103.  et al. 2008. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205:2409–17 [Google Scholar]
  104. Pirola L, Balcerczyk A, Tothill RW, Haviv I, Kaspi A. 104.  et al. 2011. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res 21:1601–15 [Google Scholar]
  105. Susick L, Senanayake T, Veluthakal R, Woster PM, Kowluru A. 105.  2009. A novel histone deacetylase inhibitor prevents IL-1β induced metabolic dysfunction in pancreatic β-cells. J. Cell. Mol. Med. 13:1877–85 [Google Scholar]
  106. Lewis EC, Blaabjerg L, Størling J, Ronn SG, Mascagni P. 106.  et al. 2011. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. Mol. Med. 17:369–77 [Google Scholar]
  107. Galmozzi A, Mitro N, Ferrari A, Gers E, Gilardi F. 107.  et al. 2013. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 62:732–42 [Google Scholar]
  108. Bardelli A, Pantel K. 108.  2017. Liquid biopsies, what we do not know (yet). Cancer Cell 31:172–79 [Google Scholar]
  109. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO. 109.  et al. 2001. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61:1659–65 [Google Scholar]
  110. Diehl F, Li M, Dressman D, He YP, Shen D. 110.  et al. 2005. Detection and quantification of mutations in the plasma of patients with colorectal tumors. PNAS 102:16368–73 [Google Scholar]
  111. Schwarzenbach H, Stoehlmacher J, Pantel K, Goekkurt E. 111.  2008. Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer. Ann. N.Y. Acad. Sci. 1137:190–96 [Google Scholar]
  112. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y. 112.  et al. 2014. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6:224ra24 [Google Scholar]
  113. Herbst A, Vdovin N, Gacesa S, Philipp A, Nagel D. 113.  et al. 2017. Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer. Int. J. Cancer 140:2134–44 [Google Scholar]
  114. Nian J, Sun X, Ming S, Yan C, Ma Y. 114.  et al. 2017. Diagnostic accuracy of methylated SEPT9 for blood-based colorectal cancer detection: a systematic review and meta-analysis. Clin. Transl. Gastroenterol. 8:e216 [Google Scholar]
  115. Lauschke VM, Ivanov M, Ingelman-Sundberg M. 115.  2017. Pitfalls and opportunities for epigenomic analyses focused on disease diagnosis, prognosis and therapy. Trends Pharm. Sci. 38:765–70 [Google Scholar]
  116. Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J. 116.  2016. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 164:57–68 [Google Scholar]
  117. Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J. 117.  et al. 2016. Identification of tissue-specific cell death using methylation patterns of circulating DNA. PNAS 113:E1826–34 [Google Scholar]
  118. Guo S, Diep D, Plongthongkum N, Fung H-L, Zhang K, Zhang K. 118.  2017. Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA. Nat. Genet. 49:635–42 [Google Scholar]
  119. Chen L, Ge B, Casale FP, Vasquez L, Kwan T. 119.  et al. 2016. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell 167:1398–414 [Google Scholar]
  120. Sharma G, Mirza S, Parshad R, Gupta SD, Ralhan R. 120.  2012. DNA methylation of circulating DNA: a marker for monitoring efficacy of neoadjuvant chemotherapy in breast cancer patients. Tumor Biol 33:1837–43 [Google Scholar]
  121. Fiegl H, Millinger S, Mueller-Holzner E, Marth C, Ensinger C. 121.  et al. 2005. Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res 65:1141–45 [Google Scholar]
  122. Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC. 122.  et al. 2017. Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 Prospective Biomarker Study. J. Clin. Oncol. 35:751–58 [Google Scholar]
  123. Mahon KL, Qu W, Devaney J, Paul C, Castillo L. 123.  et al. 2014. Methylated glutathione s-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer. Br. J. Cancer 111:1802–9 [Google Scholar]
  124. Ramirez JL, Rosell R, Taron M, Sanchez-Ronco M, Alberola V. 124.  et al. 2005. 14-3-3σ methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: the Spanish Lung Cancer Group. J. Clin. Oncol. 23:9105–12 [Google Scholar]
  125. Salazar F, Molina MA, Sanchez-Ronco M, Moran T, Ramirez JL. 125.  et al. 2011. First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients. Lung Cancer 72:84–91 [Google Scholar]
  126. Wang H, Zhang B, Chen D, Xia W, Zhang J. 126.  et al. 2015. Real-time monitoring efficiency and toxicity of chemotherapy in patients with advanced lung cancer. Clin. Epigenetics 7:119 [Google Scholar]
  127. Herbst A, Vdovin N, Gacesa S, Philipp A, Nagel D. 127.  et al. 2017. Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer. Int. J. Cancer 140:2134–44 [Google Scholar]
  128. Mori T, O'Day SJ, Umetani N, Martinez SR, Kitago M. 128.  et al. 2005. Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. J. Clin. Oncol. 23:9351–58 [Google Scholar]
  129. Gifford G, Paul J, Vasey PA, Kaye SB, Brown R. 129.  2004. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin. Cancer Res. 10:4420–26 [Google Scholar]
  130. 130. Novartis. 2013. Predictive markers useful in the diagnosis and treatment of fragile x syndrome (fxs) Patent No. WO2103131981A1
  131. Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E. 131.  et al. 2011. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3:64ra1 [Google Scholar]
  132. Issa J-PJ, Roboz G, Rizzieri D, Jabbour E, Stock W. 132.  et al. 2015. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 16:1099–110 [Google Scholar]
  133. Winquist E, Knox J, Ayoub J-P, Wood L, Wainman N. 133.  et al. 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. Investig. New Drugs 24:159–67 [Google Scholar]
  134. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. 134.  2007. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247–52 [Google Scholar]
  135. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E. 135.  et al. 2011. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J. Clin. Oncol. 29:2052–59 [Google Scholar]
  136. Foss F, Advani R, Duvic M, Hymes KB, Intragumtornchai T. 136.  et al. 2014. A phase II trial of belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br. J. Haematol. 168:811–19 [Google Scholar]
  137. Vitfell-Rasmussen J, Judson I, Safwat A, Jones RL, Rossen PB. 137.  et al. 2016. A phase I/II clinical trial of belinostat (PXD101) in combination with doxorubicin in patients with soft tissue sarcomas. Sarcoma 2016:2090271 [Google Scholar]
  138. Child F, Ortiz-Romero PL, Alvarez R, Bagot M, Stadler R. 138.  et al. 2016. Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome. Br. J. Dermatol. 175:80–88 [Google Scholar]
  139. Evens AM, Balasubramanian S, Vose JM, Harb W, Gordon LI. 139.  et al. 2016. A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. Clin. Cancer Res. 22:1059–66 [Google Scholar]
  140. Novotny-Diermayr V, Sangthongpitag K, Hu CY, Wu X, Sausgruber N. 140.  et al. 2010. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol. Cancer Ther. 9:642–52 [Google Scholar]
  141. Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN. 141.  et al. 2013. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor–positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. 31:2128–35 [Google Scholar]
  142. Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC. 142.  et al. 2008. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol. Cancer Ther. 7:759–68 [Google Scholar]
  143. Galloway TJ, Wirth LJ, Colevas AD, Gilbert J, Bauman JE. 143.  et al. 2015. A phase I study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21:1566–73 [Google Scholar]
  144. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J. 144.  et al. 2011. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 117:5827–34 [Google Scholar]
  145. Vianello P, Botrugno OA, Cappa A, Dal Zuffo R, Dessanti P. 145.  et al. 2016. Discovery of a novel inhibitor of histone lysine-specific demethylase 1A (KDM1A/LSD1) as orally active antitumor agent. J. Med. Chem. 59:1501–17 [Google Scholar]
  146. He Y-F, Li B-Z, Li Z, Liu P, Wang Y. 146.  et al. 2011. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333:1303–7 [Google Scholar]
  147. Ito S, Shen L, Dai Q, Wu SC, Collins LB. 147.  et al. 2011. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–3 [Google Scholar]
  148. Wang L, Zhou Y, Xu L, Xiao R, Lu X. 148.  et al. 2015. Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex. Nature 523:621–25 [Google Scholar]
  149. Dai Q, Sanstead PJ, Peng CS, Han D, He C, Tokmakoff A. 149.  2016. Weakened N3 hydrogen bonding by 5-formylcytosine and 5-carboxylcytosine reduces their base-pairing stability. ACS Chem. Biol. 11:470–77 [Google Scholar]
  150. Bintu L, Yong J, Antebi YE, McCue K, Kazuki Y. 150.  et al. 2016. Dynamics of epigenetic regulation at the single-cell level. Science 351:720–24 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error