Skip to main content
SpringerLink
Log in

Epigenetic Control Using Small Molecules in Cancer

  • Chapter
  • First Online:
Approaching Complex Diseases

Part of the book series: Human Perspectives in Health Sciences and Technology ((HPHST,volume 2))

Abstract

Epigenetics is defined as heritable alterations in gene expression that are not caused by changes in DNA sequence. Such normal alterations are vital for appropriate differentiation and development. However, unfavorable epigenetic alterations are usually observed in human cancers and are closely linked to the generation of malignant phenotypes; they directly induce oncogenesis and cancer progression, and are indirectly involved in cancer through mutations that are frequently detected in malignancy-associated genes. Therefore, controlling epigenetic modifications is an interesting therapeutic approach for cancer. Indeed, many small molecules modulating epigenetic mechanisms such as DNA methylation and histone modifications have been reported to bring about promising anti- tumorigenic effects on some malignancies. In this chapter, we focus on epigenetics in cancer and describe small-molecule epigenetic modulators aimed at treating cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Agarwal, P., and S.P. Jackson. 2016. G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status. Cancer Letters 380: 467–475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Allfrey, V.G., R. Faulkner, and A.E. Mirsky. 1964. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proceedings of the National Academy of Sciences of the United States of America 51: 786–794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Amato, R.J. 2007. Inhibition of DNA methylation by antisense oligonucleotide MG98 as cancer therapy. Clinical Genitourinary Cancer 5: 422–426.

    Article  CAS  PubMed  Google Scholar 

  4. Amato, R.J., J. Stephenson, S. Hotte, J. Nemunaitis, K. Belanger, G. Reid, and R.E. Martell. 2012. MG98, a second-generation DNMT1 inhibitor, in the treatment of advanced renal cell carcinoma. Cancer Investigation 30: 415–421.

    Article  CAS  PubMed  Google Scholar 

  5. Amente, S., L. Lania, and B. Majello. 2013. The histone LSD1 demethylase in stemness and cancer transcription programs. Biochimica et Biophysica Acta 1829: 981–986.

    Article  CAS  PubMed  Google Scholar 

  6. Bannister, A.J., and T. Kouzarides. 2011. Regulation of chromatin by histone modifications. Cell Research 21: 381–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barski, A., S. Cuddapah, K. Cui, T.Y. Roh, D.E. Schones, Z. Wang, G. Wei, I. Chepelev, and K. Zhao. 2007. High-resolution profiling of histone methylations in the human genome. Cell 129: 823–837.

    Article  CAS  PubMed  Google Scholar 

  8. Baylin, S.B., and P.A. Jones. 2011. A decade of exploring the cancer epigenome – biological and translational implications. Nature Reviews. Cancer 11: 726–734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. ———. 2016. Epigenetic determinants of cancer. Cold Spring Harbor Perspectives in Biology 8 (9): a019505.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Bedalov, A., T. Gatbonton, W.P. Irvine, D.E. Gottschling, and J.A. Simon. 2001. Identification of a small molecule inhibitor of Sir2p. Proceedings of the National Academy of Sciences of the United States of America 98: 15113–15118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bedford, M.T., and S.G. Clarke. 2009. Protein arginine methylation in mammals: Who, what and why. Molecular Cell 33: 1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Benevolenskaya, E.V. 2007. Histone H3K4 demethylases are essential in development and differentiation. Biochemistry and Cell Biology 85: 435–443.

    Article  CAS  PubMed  Google Scholar 

  13. Bennett, R.L., and J.D. Licht. 2018. Targeting epigenetics in cancer. Annual Review of Pharmacology and Toxicology 58: 187–207.

    Article  CAS  PubMed  Google Scholar 

  14. Berenguer-Daize, C., L. Astorgues-Xerri, E. Odore, M. Cayol, E. Cvitkovic, K. Noel, M. Bekradda, S. Mackenzie, K. Rezai, F. Lokiec, M.E. Riveiro, and L. Ouafik. 2016. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. International Journal of Cancer 139: 2047–2055.

    Article  CAS  PubMed  Google Scholar 

  15. Bernasconi, E., E. Gaudio, P. Lejeune, C. Tarantelli, L. Cascione, I. Kwee, F. Spriano, A. Rinaldi, A.A. Mensah, E. Chung, A. Stathis, S. Siegel, N. Schmees, M. Ocker, E. Zucca, B. Haendler, and F. Bertoni. 2017. Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. British Journal of Haematology 178: 936–948.

    Article  CAS  PubMed  Google Scholar 

  16. Bernstein, B.E., T.S. Mikkelsen, X. Xie, M. Kamal, D.J. Huebert, J. Cuff, B. Fry, A. Meissner, M. Wernig, K. Plath, R. Jaenisch, A. Wagschal, R. Feil, S.L. Schreiber, and E.S. Lander. 2006. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125: 315–326.

    Article  CAS  PubMed  Google Scholar 

  17. Bertino, E.M., and G.A. Otterson. 2011. Romidepsin: A novel histone deacetylase inhibitor for cancer. Expert Opinion on Investigational Drugs 20: 1151–1158.

    Article  CAS  PubMed  Google Scholar 

  18. Bestor, T.H. 2000. The DNA methyltransferases of mammals. Human Molecular Genetics 9: 2395–2402.

    Article  CAS  PubMed  Google Scholar 

  19. Bestor, T., A. Laudano, R. Mattaliano, and V. Ingram. 1988. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. Journal of Molecular Biology 203: 971–983.

    Article  CAS  PubMed  Google Scholar 

  20. Bilen, M.A., S. Fu, G.S. Falchook, C.S. Ng, J.J. Wheler, M. Abdelrahim, B. Erguvan-Dogan, D.S. Hong, A.M. Tsimberidou, R. Kurzrock, and A. Naing. 2015. Phase I trial of valproic acid and lenalidomide in patients with advanced cancer. Cancer Chemotherapy and Pharmacology 75: 869–874.

    Article  CAS  PubMed  Google Scholar 

  21. Bird, A. 2007. Perceptions of epigenetics. Nature 447: 396–398.

    Article  CAS  PubMed  Google Scholar 

  22. Biswas, S., and C.M. Rao. 2017. Epigenetics in cancer: Fundamentals and beyond. Pharmacology & Therapeutics 173: 118–134.

    Article  CAS  Google Scholar 

  23. ———. 2018. Epigenetic tools (the writers, the readers and the erasers) and their implications in cancer therapy. European Journal of Pharmacology 837: 8–24.

    Article  CAS  PubMed  Google Scholar 

  24. Bonday, Z.Q., G.S. Cortez, M.J. Grogan, S. Antonysamy, K. Weichert, W.P. Bocchinfuso, F. Li, S. Kennedy, B. Li, M.M. Mader, C.H. Arrowsmith, P.J. Brown, M.S. Eram, M.M. Szewczyk, D. Barsyte-Lovejoy, M. Vedadi, E. Guccione, and R.M. Campbell. 2018. LLY-283, a potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activity. ACS Medicinal Chemistry Letters 9: 612–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brueckner, B., R. Garcia Boy, P. Siedlecki, T. Musch, H.C. Kliem, P. Zielenkiewicz, S. Suhai, M. Wiessler, and F. Lyko. 2005. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Research 65: 6305–6311.

    Article  CAS  PubMed  Google Scholar 

  26. Brueckner, B., M. Rius, M.R. Markelova, I. Fichtner, P.A. Hals, M.L. Sandvold, and F. Lyko. 2010. Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Molecular Cancer Therapeutics 9: 1256–1264.

    Article  CAS  PubMed  Google Scholar 

  27. Brunetto, A.T., J.E. Ang, R. Lal, D. Olmos, L.R. Molife, R. Kristeleit, A. Parker, I. Casamayor, M. Olaleye, A. Mais, B. Hauns, V. Strobel, B. Hentsch, and J.S. De Bono. 2013. First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors. Clinical Cancer Research 19: 5494–5504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bui, M.H., X. Lin, D.H. Albert, L. Li, L.T. Lam, E.J. Faivre, S.E. Warder, X. Huang, D. Wilcox, C.K. Donawho, G.S. Sheppard, L. Wang, S. Fidanze, J.K. Pratt, D. Liu, L. Hasvold, T. Uziel, X. Lu, F. Kohlhapp, G. Fang, S.W. Elmore, S.H. Rosenberg, K.F. Mcdaniel, W.M. Kati, and Y. Shen. 2017. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Research 77: 2976–2989.

    Article  CAS  PubMed  Google Scholar 

  29. Busch, C., M. Burkard, C. Leischner, U.M. Lauer, J. Frank, and S. Venturelli. 2015. Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clinical Epigenetics 7: 64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Cedar, H., and Y. Bergman. 2009. Linking DNA methylation and histone modification: Patterns and paradigms. Nature Reviews. Genetics 10: 295–304.

    Article  CAS  PubMed  Google Scholar 

  31. Chaidos, A., V. Caputo, K. Gouvedenou, B. Liu, I. Marigo, M.S. Chaudhry, A. Rotolo, D.F. Tough, N.N. Smithers, A.K. Bassil, T.D. Chapman, N.R. Harker, O. Barbash, P. Tummino, N. Al-Mahdi, A.C. Haynes, L. Cutler, B. Le, A. Rahemtulla, I. Roberts, M. Kleijnen, J.J. Witherington, N.J. Parr, R.K. Prinjha, and A. Karadimitris. 2014. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123: 697–705.

    Article  CAS  PubMed  Google Scholar 

  32. Chang, B., Y. Chen, Y. Zhao, and R.K. Bruick. 2007. JMJD6 is a histone arginine demethylase. Science 318: 444–447.

    Article  CAS  PubMed  Google Scholar 

  33. Chan-Penebre, E., K.G. Kuplast, C.R. Majer, P.A. Boriack-Sjodin, T.J. Wigle, L.D. Johnston, N. Rioux, M.J. Munchhof, L. Jin, S.L. Jacques, K.A. West, T. Lingaraj, K. Stickland, S.A. Ribich, A. Raimondi, M.P. Scott, N.J. Waters, R.M. Pollock, J.J. Smith, O. Barbash, M. Pappalardi, T.F. Ho, K. Nurse, K.P. Oza, K.T. Gallagher, R. Kruger, M.P. Moyer, R.A. Copeland, R. Chesworth, and K.W. Duncan. 2015. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nature Chemical Biology 11: 432–437.

    Article  CAS  PubMed  Google Scholar 

  34. Chen, J.S., D.V. Faller, and R.A. Spanjaard. 2003. Short-chain fatty acid inhibitors of histone deacetylases: Promising anticancer therapeutics? Current Cancer Drug Targets 3: 219–236.

    Article  CAS  PubMed  Google Scholar 

  35. Cheung, N., T.K. Fung, B.B. Zeisig, K. Holmes, J.K. Rane, K.A. Mowen, M.G. Finn, B. Lenhard, L.C. Chan, and C.W. So. 2016. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell 29: 32–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Choi, W.J., H.J. Chung, G. Chandra, V. Alexander, L.X. Zhao, H.W. Lee, A. Nayak, M.S. Majik, H.O. Kim, J.H. Kim, Y.B. Lee, C.H. Ahn, S.K. Lee, and L.S. Jeong. 2012. Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity. Journal of Medicinal Chemistry 55: 4521–4525.

    Article  CAS  PubMed  Google Scholar 

  37. Chung, C.W., H. Coste, J.H. White, O. Mirguet, J. Wilde, R.L. Gosmini, C. Delves, S.M. Magny, R. Woodward, S.A. Hughes, E.V. Boursier, H. Flynn, A.M. Bouillot, P. Bamborough, J.M. Brusq, F.J. Gellibert, E.J. Jones, A.M. Riou, P. Homes, S.L. Martin, I.J. Uings, J. Toum, C.A. Clement, A.B. Boullay, R.L. Grimley, F.M. Blandel, R.K. Prinjha, K. Lee, J. Kirilovsky, and E. Nicodeme. 2011. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. Journal of Medicinal Chemistry 54: 3827–3838.

    Article  CAS  PubMed  Google Scholar 

  38. Constantinides, P.G., P.A. Jones, and W. Gevers. 1977. Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature 267: 364–366.

    Article  CAS  PubMed  Google Scholar 

  39. Cortellino, S., J. Xu, M. Sannai, R. Moore, E. Caretti, A. Cigliano, M. Le Coz, K. Devarajan, A. Wessels, D. Soprano, L.K. Abramowitz, M.S. Bartolomei, F. Rambow, M.R. Bassi, T. Bruno, M. Fanciulli, C. Renner, A.J. Klein-Szanto, Y. Matsumoto, D. Kobi, I. Davidson, C. Alberti, L. Larue, and A. Bellacosa. 2011. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146: 67–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cote, J., and S. Richard. 2005. Tudor domains bind symmetrical dimethylated arginines. The Journal of Biological Chemistry 280: 28476–28483.

    Article  CAS  PubMed  Google Scholar 

  41. Datta, J., K. Ghoshal, W.A. Denny, S.A. Gamage, D.G. Brooke, P. Phiasivongsa, S. Redkar, and S.T. Jacob. 2009. A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Research 69: 4277–4285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Derissen, E.J., J.H. Beijnen, and J.H. Schellens. 2013. Concise drug review: Azacitidine and decitabine. The Oncologist 18: 619–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Doroshow, D.B., J.P. Eder, and P.M. Lorusso. 2017. BET inhibitors: A novel epigenetic approach. Annals of Oncology 28: 1776–1787.

    Article  CAS  PubMed  Google Scholar 

  44. Drew, A.E., O. Moradei, S.L. Jacques, N. Rioux, A.P. Boriack-Sjodin, C. Allain, M.P. Scott, L. Jin, A. Raimondi, J.L. Handler, H.M. Ott, R.G. Kruger, M.T. Mccabe, C. Sneeringer, T. Riera, G. Shapiro, N.J. Waters, L.H. Mitchell, K.W. Duncan, M.P. Moyer, R.A. Copeland, J. Smith, R. Chesworth, and S.A. Ribich. 2017. Identification of a CARM1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma. Scientific Reports 7: 17993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Du, Q., P.L. Luu, C. Stirzaker, and S.J. Clark. 2015. Methyl-CpG-binding domain proteins: Readers of the epigenome. Epigenomics 7: 1051–1073.

    Article  CAS  PubMed  Google Scholar 

  46. Duque-Afonso, J., A. Yalcin, T. Berg, M. Abdelkarim, O. Heidenreich, and M. Lubbert. 2011. The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO. Oncogene 30: 3062–3072.

    Article  CAS  PubMed  Google Scholar 

  47. Easwaran, H., S.E. Johnstone, L. Van Neste, J. Ohm, T. Mosbruger, Q. Wang, M.J. Aryee, P. Joyce, N. Ahuja, D. Weisenberger, E. Collisson, J. Zhu, S. Yegnasubramanian, W. Matsui, and S.B. Baylin. 2012. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Research 22: 837–849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Easwaran, H., H.C. Tsai, and S.B. Baylin. 2014. Cancer epigenetics: Tumor heterogeneity, plasticity of stem-like states, and drug resistance. Molecular Cell 54: 716–727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Egger, G., G. Liang, A. Aparicio, and P.A. Jones. 2004. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429: 457–463.

    Article  CAS  PubMed  Google Scholar 

  50. Eissenberg, J.C., and A. Shilatifard. 2010. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Developmental Biology 339: 240–249.

    Article  CAS  PubMed  Google Scholar 

  51. Emami, K.H., C. Nguyen, H. Ma, D.H. Kim, K.W. Jeong, M. Eguchi, R.T. Moon, J.L. Teo, H.Y. Kim, S.H. Moon, J.R. Ha, and M. Kahn. 2004. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proceedings of the National Academy of Sciences of the United States of America 101: 12682–12687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ernst, T., A.J. Chase, J. Score, C.E. Hidalgo-Curtis, C. Bryant, A.V. Jones, K. Waghorn, K. Zoi, F.M. Ross, A. Reiter, A. Hochhaus, H.G. Drexler, A. Duncombe, F. Cervantes, D. Oscier, J. Boultwood, F.H. Grand, and N.C. Cross. 2010. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genetics 42: 722–726.

    Article  CAS  PubMed  Google Scholar 

  53. Esteller, M. 2007. Cancer epigenomics: DNA methylomes and histone-modification maps. Nature Reviews. Genetics 8: 286–298.

    Article  CAS  PubMed  Google Scholar 

  54. Evens, A.M., S. Balasubramanian, J.M. Vose, W. Harb, L.I. Gordon, R. Langdon, J. Sprague, M. Sirisawad, C. Mani, J. Yue, Y. Luan, S. Horton, T. Graef, and N.L. Bartlett. 2016. A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. Clinical Cancer Research 22: 1059–1066.

    Article  CAS  PubMed  Google Scholar 

  55. Fang, M.Z., Y. Wang, N. Ai, Z. Hou, Y. Sun, H. Lu, W. Welsh, and C.S. Yang. 2003. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Research 63: 7563–7570.

    CAS  PubMed  Google Scholar 

  56. Feinberg, A.P., and B. Vogelstein. 1983. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301: 89–92.

    Article  CAS  PubMed  Google Scholar 

  57. Filippakopoulos, P., J. Qi, S. Picaud, Y. Shen, W.B. Smith, O. Fedorov, E.M. Morse, T. Keates, T.T. Hickman, I. Felletar, M. Philpott, S. Munro, M.R. Mckeown, Y. Wang, A.L. Christie, N. West, M.J. Cameron, B. Schwartz, T.D. Heightman, N. La Thangue, C.A. French, O. Wiest, A.L. Kung, S. Knapp, and J.E. Bradner. 2010. Selective inhibition of BET bromodomains. Nature 468: 1067–1073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Filippakopoulos, P., S. Picaud, M. Mangos, T. Keates, J.P. Lambert, D. Barsyte-Lovejoy, I. Felletar, R. Volkmer, S. Muller, T. Pawson, A.C. Gingras, C.H. Arrowsmith, and S. Knapp. 2012. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149: 214–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Furdas, S.D., S. Kannan, W. Sippl, and M. Jung. 2012. Small molecule inhibitors of histone acetyltransferases as epigenetic tools and drug candidates. Archiv der Pharmazie (Weinheim) 345: 7–21.

    Article  CAS  Google Scholar 

  60. Furlan, A., V. Monzani, L.L. Reznikov, F. Leoni, G. Fossati, D. Modena, P. Mascagni, and C.A. Dinarello. 2011. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Molecular Medicine 17: 353–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gajer, J.M., S.D. Furdas, A. Grunder, M. Gothwal, U. Heinicke, K. Keller, F. Colland, S. Fulda, H.L. Pahl, I. Fichtner, W. Sippl, and M. Jung. 2015. Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo. Oncogene 4: e137.

    Article  CAS  Google Scholar 

  62. Gao, C., E. Bourke, M. Scobie, M.A. Famme, T. Koolmeister, T. Helleday, L.A. Eriksson, N.F. Lowndes, and J.A. Brown. 2014. Rational design and validation of a Tip60 histone acetyltransferase inhibitor. Scientific Reports 4: 5372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Garcia-Manero, G., E. Atallah, S.K. Khaled, M. Arellano, M.M. Patnaik, T.A. Butler, C. Ashby, and B.C. Medeiros. 2015. Final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia (AML). Blood 126 (3): –453.

    Google Scholar 

  64. Garraway, L.A., and E.S. Lander. 2013. Lessons from the cancer genome. Cell 153: 17–37.

    Article  CAS  PubMed  Google Scholar 

  65. Gatzka, M.V. 2018. Targeted tumor therapy remixed-an update on the use of small-molecule drugs in combination therapies. Cancers (Basel) 10 (6).

    Google Scholar 

  66. Ghizzoni, M., J. Wu, T. Gao, H.J. Haisma, F.J. Dekker, and Y. George Zheng. 2012. 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site. European Journal of Medicinal Chemistry 47: 337–344.

    Article  CAS  PubMed  Google Scholar 

  67. Ghoshal, K., J. Datta, S. Majumder, S. Bai, H. Kutay, T. Motiwala, and S.T. Jacob. 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. Molecular and Cellular Biology 25: 4727–4741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gibney, E.R., and C.M. Nolan. 2010. Epigenetics and gene expression. Heredity (Edinburgh) 105: 4–13.

    Article  CAS  Google Scholar 

  69. Graca, I., E.J. Sousa, P. Costa-Pinheiro, F.Q. Vieira, J. Torres-Ferreira, M.G. Martins, R. Henrique, and C. Jeronimo. 2014. Anti-neoplastic properties of hydralazine in prostate cancer. Oncotarget 5: 5950–5964.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Gronbaek, K., C. Hother, and P.A. Jones. 2007. Epigenetic changes in cancer. APMIS 115: 1039–1059.

    Article  PubMed  Google Scholar 

  71. Gupta, S., K. Doyle, T.L. Mosbruger, A. Butterfield, A. Weston, A. Ast, M. Kaadige, A. Verma, and S. Sharma. 2018. Reversible LSD1 inhibition with HCI-2509 induces the p53 gene expression signature and disrupts the MYCN signature in high-risk neuroblastoma cells. Oncotarget 9: 9907–9924.

    PubMed  PubMed Central  Google Scholar 

  72. Hamada, S., T. Suzuki, K. Mino, K. Koseki, F. Oehme, I. Flamme, H. Ozasa, Y. Itoh, D. Ogasawara, H. Komaarashi, A. Kato, H. Tsumoto, H. Nakagawa, M. Hasegawa, R. Sasaki, T. Mizukami, and N. Miyata. 2010. Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors. Journal of Medicinal Chemistry 53: 5629–5638.

    Article  CAS  PubMed  Google Scholar 

  73. Hamburger, A.W., and S.E. Salmon. 1977. Primary bioassay of human tumor stem cells. Science 197: 461–463.

    Article  CAS  PubMed  Google Scholar 

  74. Hancock, R.L., K. Dunne, L.J. Walport, E. Flashman, and A. Kawamura. 2015. Epigenetic regulation by histone demethylases in hypoxia. Epigenomics 7: 791–811.

    Article  CAS  PubMed  Google Scholar 

  75. Hashimoto, H., P.M. Vertino, and X. Cheng. 2010. Molecular coupling of DNA methylation and histone methylation. Epigenomics 2: 657–669.

    Article  CAS  PubMed  Google Scholar 

  76. Hauser, A.T., D. Robaa, and M. Jung. 2018. Epigenetic small molecule modulators of histone and DNA methylation. Current Opinion in Chemical Biology 45: 73–85.

    Article  CAS  PubMed  Google Scholar 

  77. Hay, D.A., O. Fedorov, S. Martin, D.C. Singleton, C. Tallant, C. Wells, S. Picaud, M. Philpott, O.P. Monteiro, C.M. Rogers, S.J. Conway, T.P. Rooney, A. Tumber, C. Yapp, P. Filippakopoulos, M.E. Bunnage, S. Muller, S. Knapp, C.J. Schofield, and P.E. Brennan. 2014. Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains. Journal of the American Chemical Society 136: 9308–9319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Heinemann, B., J.M. Nielsen, H.R. Hudlebusch, M.J. Lees, D.V. Larsen, T. Boesen, M. Labelle, L.O. Gerlach, P. Birk, and K. Helin. 2014. Inhibition of demethylases by GSK-J1/J4. Nature 514: E1–E2.

    Article  CAS  PubMed  Google Scholar 

  79. Heltweg, B., T. Gatbonton, A.D. Schuler, J. Posakony, H. Li, S. Goehle, R. Kollipara, R.A. Depinho, Y. Gu, J.A. Simon, and A. Bedalov. 2006. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Research 66: 4368–4377.

    Article  CAS  PubMed  Google Scholar 

  80. Herold, J.M., T.J. Wigle, J.L. Norris, R. Lam, V.K. Korboukh, C. Gao, L.A. Ingerman, D.B. Kireev, G. Senisterra, M. Vedadi, A. Tripathy, P.J. Brown, C.H. Arrowsmith, J. Jin, W.P. Janzen, and S.V. Frye. 2011. Small-molecule ligands of methyl-lysine binding proteins. Journal of Medicinal Chemistry 54: 2504–2511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Herold, J.M., L.I. James, V.K. Korboukh, C. Gao, K.E. Coil, D.J. Bua, J.L. Norris, D.B. Kireev, P.J. Brown, J. Jin, W.P. Janzen, O. Gozani, and S.V. Frye. 2012. Structure-activity relationships of methyl-lysine reader antagonists. Medchemcomm 3: 45–51.

    Article  CAS  Google Scholar 

  82. Hodawadekar, S.C., and R. Marmorstein. 2007. Chemistry of acetyl transfer by histone modifying enzymes: Structure, mechanism and implications for effector design. Oncogene 26: 5528–5540.

    Article  CAS  PubMed  Google Scholar 

  83. Hopkinson, R.J., A. Tumber, C. Yapp, R. Chowdhury, W. Aik, K.H. Che, X.S. Li, J.B.L. Kristensen, O.N.F. King, M.C. Chan, K.K. Yeoh, H. Choi, L.J. Walport, C.C. Thinnes, J.T. Bush, C. Lejeune, A.M. Rydzik, N.R. Rose, E.A. Bagg, M.A. Mcdonough, T. Krojer, W.W. Yue, S.S. Ng, L. Olsen, P.E. Brennan, U. Oppermann, S. Muller-Knapp, R.J. Klose, P.J. Ratcliffe, C.J. Schofield, and A. Kawamura. 2013a. 5-carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation. Chemical Science 4: 3110–3117.

    Article  CAS  PubMed  Google Scholar 

  84. Hopkinson, R.J., A. Tumber, C. Yapp, R. Chowdhury, W. Aik, K.H. Che, X.S. Li, J.B.L. Kristensen, O.N.F. King, M.C. Chan, K.K. Yeoh, H. Choi, L.J. Walport, C.C. Thinnes, J.T. Bush, C. Lejeune, A.M. Rydzik, N.R. Rose, E.A. Bagg, M.A. Mcdonough, T.J. Krojer, W.W. Yue, S.S. Ng, L. Olsen, P.E. Brennan, U. Oppermann, S. Muller, R.J. Klose, P.J. Ratcliffe, C.J. Schofield, and A. Kawamura. 2013b. 5-Carboxy-8- hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation. Chemical Science 4: 3110–3117.

    Article  CAS  PubMed  Google Scholar 

  85. Hore, T.A., F. Von Meyenn, M. Ravichandran, M. Bachman, G. Ficz, D. Oxley, F. Santos, S. Balasubramanian, T.P. Jurkowski, and W. Reik. 2016. Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naive pluripotency by complementary mechanisms. Proceedings of the National Academy of Sciences of the United States of America 113: 12202–12207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Huang, Y., and A. Rao. 2014. Connections between TET proteins and aberrant DNA modification in cancer. Trends in Genetics 30: 464–474.

    Article  CAS  PubMed  Google Scholar 

  87. Huang, Y., Greene, E., Murray Stewart, T., Goodwin, A. C., Baylin, S. B., Woster, P. M. & Casero, R. A., JR. (2007) Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proceedings of the National Academy of Sciences of the United States of America, 104, 8023-8028.

    Google Scholar 

  88. Huntly, B.J., and D.G. Gilliland. 2005. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nature Reviews. Cancer 5: 311–321.

    Article  CAS  PubMed  Google Scholar 

  89. Imai, S., C.M. Armstrong, M. Kaeberlein, and L. Guarente. 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800.

    Article  CAS  PubMed  Google Scholar 

  90. Ito, S., A.C. D’alessio, O.V. Taranova, K. Hong, L.C. Sowers, and Y. Zhang. 2010. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466: 1129–1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Itoh, Y. 2018. Chemical protein degradation approach and its application to epigenetic targets. Chemical Record 18: 1681–1700.

    Article  CAS  PubMed  Google Scholar 

  92. Itoh, Y., T. Suzuki, and N. Miyata. 2013. Small-molecular modulators of cancer-associated epigenetic mechanisms. Molecular BioSystems 9: 873–896.

    Article  CAS  PubMed  Google Scholar 

  93. James, L.I., D. Barsyte-Lovejoy, N. Zhong, L. Krichevsky, V.K. Korboukh, J.M. Herold, C.J. Macnevin, J.L. Norris, C.A. Sagum, W. Tempel, E. Marcon, H. Guo, C. Gao, X.P. Huang, S. Duan, A. Emili, J.F. Greenblatt, D.B. Kireev, J. Jin, W.P. Janzen, P.J. Brown, M.T. Bedford, C.H. Arrowsmith, and S.V. Frye. 2013a. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nature Chemical Biology 9: 184–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. James, L.I., V.K. Korboukh, L. Krichevsky, B.M. Baughman, J.M. Herold, J.L. Norris, J. Jin, D.B. Kireev, W.P. Janzen, C.H. Arrowsmith, and S.V. Frye. 2013b. Small-molecule ligands of methyl-lysine binding proteins: Optimization of selectivity for L3MBTL3. Journal of Medicinal Chemistry 56: 7358–7371.

    Article  CAS  PubMed  Google Scholar 

  95. Jeanmougin, F., Wurtz, J. M., LE Douarin, B., Chambon, P. & Losson, R. (1997) The bromodomain revisited. Trends in Biochemical Sciences, 22, 151-153.

    Google Scholar 

  96. Jenuwein, T., and C.D. Allis. 2001. Translating the histone code. Science 293: 1074–1080.

    Article  CAS  PubMed  Google Scholar 

  97. Jing, H., J. Hu, B. He, Y.L. Negron Abril, J. Stupinski, K. Weiser, M. Carbonaro, Y.L. Chiang, T. Southard, P. Giannakakou, R.S. Weiss, and H. Lin. 2016. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 29: 767–768.

    Article  CAS  PubMed  Google Scholar 

  98. Jones, P.A., and S.B. Baylin. 2007. The epigenomics of cancer. Cell 128: 683–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kaniskan, H.U., M.L. Martini, and J. Jin. 2018. Inhibitors of protein methyltransferases and demethylases. Chemical Reviews 118: 989–1068.

    Article  CAS  PubMed  Google Scholar 

  100. Kantarjian, H.M., G.J. Roboz, P.L. Kropf, K.W.L. Yee, C.L. O’Connell, R. Tibes, K.J. Walsh, N.A. Podoltsev, E.A. Griffiths, E. Jabbour, G. Garcia-Manero, D. Rizzieri, W. Stock, M.R. Savona, T.L. Rosenblat, J.G. Berdeja, F. Ravandi, E.P. Rock, Y. Hao, M. Azab, and J.J. Issa. 2017. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: Phase 2 results from a multicentre, randomised, phase 1/2 trial. The Lancet Oncology 18: 1317–1326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kim, K.H., and C.W. Roberts. 2016. Targeting EZH2 in cancer. Nature Medicine 22: 128–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim, H.W., S.A. Kim, and S.G. Ahn. 2016. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. Oncology Reports 35: 235–242.

    Article  CAS  PubMed  Google Scholar 

  103. Kouzarides, T. 2007. Chromatin modifications and their function. Cell 128: 693–705.

    Article  CAS  PubMed  Google Scholar 

  104. Kozako, T., A. Aikawa, T. Shoji, T. Fujimoto, M. Yoshimitsu, S. Shirasawa, H. Tanaka, S. Honda, H. Shimeno, N. Arima, and S. Soeda. 2012. High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells. International Journal of Cancer 131: 2044–2055.

    Article  CAS  PubMed  Google Scholar 

  105. Kozako, T., T. Suzuki, M. Yoshimitsu, N. Arima, S.I. Honda, and S. Soeda. 2014. Anticancer agents targeted to sirtuins. Molecules 19: 20295–20313.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Kozako, T., T. Suzuki, M. Yoshimitsu, Y. Uchida, A. Kuroki, A. Aikawa, S. Honda, N. Arima, and S. Soeda. 2015. Novel small-molecule SIRT1 inhibitors induce cell death in adult T-cell leukaemia cells. Scientific Reports 5: 11345.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kozako, T., P. Mellini, T. Ohsugi, A. Aikawa, Y.I. Uchida, S.I. Honda, and T. Suzuki. 2018. Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines. BMC Cancer 18: 791.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Krause, C.D., Z.H. Yang, Y.S. Kim, J.H. Lee, J.R. Cook, and S. Pestka. 2007. Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacology & Therapeutics 113: 50–87.

    Article  CAS  Google Scholar 

  109. Kubicek, S., R.J. O’Sullivan, E.M. August, E.R. Hickey, Q. Zhang, M.L. Teodoro, S. Rea, K. Mechtler, J.A. Kowalski, C.A. Homon, T.A. Kelly, and T. Jenuwein. 2007. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Molecular Cell 25: 473–481.

    Article  CAS  PubMed  Google Scholar 

  110. Kuck, D., T. Caulfield, F. Lyko, and J.L. Medina-Franco. 2010a. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Molecular Cancer Therapeutics 9: 3015–3023.

    Article  CAS  PubMed  Google Scholar 

  111. Kuck, D., N. Singh, F. Lyko, and J.L. Medina-Franco. 2010b. Novel and selective DNA methyltransferase inhibitors: docking-based virtual screening and experimental evaluation. Bioorganic & Medicinal Chemistry 18: 822–829.

    Article  CAS  Google Scholar 

  112. Kuntz, K.W., J.E. Campbell, H. Keilhack, R.M. Pollock, S.K. Knutson, M. Porter-Scott, V.M. Richon, C.J. Sneeringer, T.J. Wigle, C.J. Allain, C.R. Majer, M.P. Moyer, R.A. Copeland, and R. Chesworth. 2016. The importance of being me: Magic methyls, methyltransferase inhibitors, and the discovery of tazemetostat. Journal of Medicinal Chemistry 59: 1556–1564.

    Article  CAS  PubMed  Google Scholar 

  113. Kwok, J., M. O’shea, D.A. Hume, and A. Lengeling. 2017. Jmjd6, a JmjC dioxygenase with many interaction partners and pleiotropic functions. Frontiers in Genetics 8: 32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lain, S., J.J. Hollick, J. Campbell, O.D. Staples, M. Higgins, M. Aoubala, A. Mccarthy, V. Appleyard, K.E. Murray, L. Baker, A. Thompson, J. Mathers, S.J. Holland, M.J. Stark, G. Pass, J. Woods, D.P. Lane, and N.J. Westwood. 2008. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13: 454–463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lara, E., A. Mai, V. Calvanese, L. Altucci, P. Lopez-Nieva, M.L. Martinez-Chantar, M. Varela-Rey, D. Rotili, A. Nebbioso, S. Ropero, G. Montoya, J. Oyarzabal, S. Velasco, M. Serrano, M. Witt, A. Villar-Garea, A. Imhof, J.M. Mato, M. Esteller, and M.F. Fraga. 2009. Salermide, a sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene 28: 781–791.

    Article  CAS  PubMed  Google Scholar 

  116. Leal, A.S., C.R. Williams, D.B. Royce, P.A. Pioli, M.B. Sporn, and K.T. Liby. 2017. Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer. Cancer Letters 394: 76–87.

    Article  CAS  PubMed  Google Scholar 

  117. Lee, K.K., and J.L. Workman. 2007. Histone acetyltransferase complexes: One size doesn’t fit all. Nature Reviews. Molecular Cell Biology 8: 284–295.

    Article  CAS  PubMed  Google Scholar 

  118. Lee, B.H., S. Yegnasubramanian, X. Lin, and W.G. Nelson. 2005. Procainamide is a specific inhibitor of DNA methyltransferase 1. The Journal of Biological Chemistry 280: 40749–40756.

    Article  CAS  PubMed  Google Scholar 

  119. Lee, H.Z., V.E. Kwitkowski, P.L. del Valle, M.S. Ricci, H. Saber, B.A. Habtemariam, J. Bullock, E. Bloomquist, Y. Li Shen, X.H. Chen, J. Brown, N. Mehrotra, S. Dorff, R. Charlab, R.C. Kane, E. Kaminskas, R. Justice, A.T. Farrell, and R. Pazdur. 2015. FDA approval: Belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clinical Cancer Research 21: 2666–2670.

    Article  CAS  PubMed  Google Scholar 

  120. Ler, L.D., S. Ghosh, X. Chai, A.A. Thike, H.L. Heng, E.Y. Siew, S. Dey, L.K. Koh, J.Q. Lim, W.K. Lim, S.S. Myint, J.L. Loh, P. Ong, X.X. Sam, D. Huang, T. Lim, P.H. Tan, S. Nagarajan, C.W. Cheng, H. Ho, L.G. Ng, J. Yuen, P.H. Lin, C.K. Chuang, Y.H. Chang, W.H. Weng, S.G. Rozen, P. Tan, C.L. Creasy, S.T. Pang, M.T. Mccabe, S.L. Poon, and B.T. Teh. 2017. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Science Translational Medicine 9, 378.

    Google Scholar 

  121. Li, P., J. Hu, and Y. Wang. 2012. Methods for analyzing histone citrullination in chromatin structure and gene regulation. Methods in Molecular Biology 809: 473–488.

    Article  CAS  PubMed  Google Scholar 

  122. Li, L.X., L.X. Fan, J.X. Zhou, J.J. Grantham, J.P. Calvet, J. Sage, and X. Li. 2017. Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease. The Journal of Clinical Investigation 127: 2751–2764.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Liu, B.L., J.X. Cheng, X. Zhang, R. Wang, W. Zhang, H. Lin, X. Xiao, S. Cai, X.Y. Chen, and H. Cheng. 2010. Global histone modification patterns as prognostic markers to classify glioma patients. Cancer Epidemiology, Biomarkers & Prevention 19: 2888–2896.

    Article  CAS  Google Scholar 

  124. Liu, W., L. Deng, Y. Song, and M. Redell. 2014. DOT1L inhibition sensitizes MLL- rearranged AML to chemotherapy. PLoS One 9: e98270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Lohse, B., A.L. Nielsen, J.B. Kristensen, C. Helgstrand, P.A. Cloos, L. Olsen, M. Gajhede, R.P. Clausen, and J.L. Kristensen. 2011. Targeting histone lysine demethylases by truncating the histone 3 tail to obtain selective substrate-based inhibitors. Angewandte Chemie (International Ed. in English) 50: 9100–9103.

    Article  CAS  Google Scholar 

  126. Luger, K., and T.J. Richmond. 1998. The histone tails of the nucleosome. Current Opinion in Genetics & Development 8: 140–146.

    Article  CAS  Google Scholar 

  127. Maes, T., E. Carceller, J. Salas, A. Ortega, and C. Buesa. 2015. Advances in the development of histone lysine demethylase inhibitors. Current Opinion in Pharmacology 23: 52–60.

    Article  CAS  PubMed  Google Scholar 

  128. Mann, B.S., J.R. Johnson, M.H. Cohen, R. Justice, and R. Pazdur. 2007. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. The Oncologist 12: 1247–1252.

    Article  CAS  PubMed  Google Scholar 

  129. Martin, L.J., M. Koegl, G. Bader, X.L. Cockcroft, O. Fedorov, D. Fiegen, T. Gerstberger, M.H. Hofmann, A.F. Hohmann, D. Kessler, S. Knapp, P. Knesl, S. Kornigg, S. Muller, H. Nar, C. Rogers, K. Rumpel, O. Schaaf, S. Steurer, C. Tallant, C.R. Vakoc, M. Zeeb, A. Zoephel, M. Pearson, G. Boehmelt, and D. Mcconnell. 2016. Structure-based design of an in vivo active selective BRD9 inhibitor. Journal of Medicinal Chemistry 59: 4462–4475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mccabe, M.T., H.M. Ott, G. Ganji, S. Korenchuk, C. Thompson, G.S. Van Aller, Y. Liu, A.P. Graves, A. Della Pietra 3rd, E. Diaz, L.V. Lafrance, M. Mellinger, C. Duquenne, X. Tian, R.G. Kruger, C.F. Mchugh, M. Brandt, W.H. Miller, D. Dhanak, S.K. Verma, P.J. Tummino, and C.L. Creasy. 2012. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492: 108–112.

    Article  CAS  PubMed  Google Scholar 

  131. Mellini, P., Y. Itoh, H. Tsumoto, Y. Li, M. Suzuki, N. Tokuda, T. Kakizawa, Y. Miura, J. Takeuchi, M. Lahtela-Kakkonen, and T. Suzuki. 2017. Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, “selectivity pocket” and NAD(+)-binding site. Chemical Science 8: 6400–6408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Milite, C., A. Feoli, K. Sasaki, V. La Pietra, A.L. Balzano, L. Marinelli, A. Mai, E. Novellino, S. Castellano, A. Tosco, and G. Sbardella. 2015. A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach. Journal of Medicinal Chemistry 58: 2779–2798.

    Article  CAS  PubMed  Google Scholar 

  133. Miller, T.C., T.J. Rutherford, K. Birchall, J. Chugh, M. Fiedler, and M. Bienz. 2014. Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger. ACS Chemical Biology 9: 2864–2874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Miranda-Goncalves, V., A. Lameirinhas, R. Henrique, and C. Jeronimo. 2018. Metabolism and epigenetic interplay in cancer: Regulation and putative therapeutic targets. Frontiers in Genetics 9: 427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Miremadi, A., M.Z. Oestergaard, P.D. Pharoah, and C. Caldas. 2007. Cancer genetics of epigenetic genes. Human Molecular Genetics 16 (Spec No 1): R28–R49.

    Google Scholar 

  136. Morin, R.D., N.A. Johnson, T.M. Severson, A.J. Mungall, J. An, R. Goya, J.E. Paul, M. Boyle, B.W. Woolcock, F. Kuchenbauer, D. Yap, R.K. Humphries, O.L. Griffith, S. Shah, H. Zhu, M. Kimbara, P. Shashkin, J.F. Charlot, M. Tcherpakov, R. Corbett, A. Tam, R. Varhol, D. Smailus, M. Moksa, Y. Zhao, A. Delaney, H. Qian, I. Birol, J. Schein, R. Moore, R. Holt, D.E. Horsman, J.M. Connors, S. Jones, S. Aparicio, M. Hirst, R.D. Gascoyne, and M.A. Marra. 2010. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genetics 42: 181–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nakagawa, M., Y. Oda, T. Eguchi, S. Aishima, T. Yao, F. Hosoi, Y. Basaki, M. Ono, M. Kuwano, M. Tanaka, and M. Tsuneyoshi. 2007. Expression profile of class I histone deacetylases in human cancer tissues. Oncology Reports 18: 769–774.

    CAS  PubMed  Google Scholar 

  138. Nakamura, K., K. Nakabayashi, K. Htet Aung, K. Aizawa, N. Hori, J. Yamauchi, K. Hata, and A. Tanoue. 2015. DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status. PLoS One 10: e0120545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Nakayama, K., M.M. Szewczyk, C. Dela Sena, H. Wu, A. Dong, H. Zeng, F. Li, R.F. De Freitas, M.S. Eram, M. Schapira, Y. Baba, M. Kunitomo, D.R. Cary, M. Tawada, A. Ohashi, Y. Imaeda, K.S. Saikatendu, C.E. Grimshaw, M. Vedadi, C.H. Arrowsmith, D. Barsyte-Lovejoy, A. Kiba, D. Tomita, and P.J. Brown. 2018. TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma. Oncotarget 9: 18480–18493.

    PubMed  PubMed Central  Google Scholar 

  140. Nguyen, H., A. Allali-Hassani, S. Antonysamy, S. Chang, L.H. Chen, C. Curtis, S. Emtage, L. Fan, T. Gheyi, F. Li, S. Liu, J.R. Martin, D. Mendel, J.B. Olsen, L. Pelletier, T. Shatseva, S. Wu, F.F. Zhang, C.H. Arrowsmith, P.J. Brown, R.M. Campbell, B.A. Garcia, D. Barsyte-Lovejoy, M. Mader, and M. Vedadi. 2015. LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2. The Journal of Biological Chemistry 290: 13641–13653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ogasawara, D., Y. Itoh, H. Tsumoto, T. Kakizawa, K. Mino, K. Fukuhara, H. Nakagawa, M. Hasegawa, R. Sasaki, T. Mizukami, N. Miyata, and T. Suzuki. 2013. Lysine-specific demethylase 1-selective inactivators: Protein-targeted drug delivery mechanism. Angewandte Chemie (International Ed. in English) 52: 8620–8624.

    Article  CAS  Google Scholar 

  142. Ohm, J.E., K.M. Mcgarvey, X. Yu, L. Cheng, K.E. Schuebel, L. Cope, H.P. Mohammad, W. Chen, V.C. Daniel, W. Yu, D.M. Berman, T. Jenuwein, K. Pruitt, S.J. Sharkis, D.N. Watkins, J.G. Herman, and S.B. Baylin. 2007. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature Genetics 39: 237–242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ohtani-Fujita, N., T. Fujita, A. Aoike, N.E. Osifchin, P.D. Robbins, and T. Sakai. 1993. CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene 8: 1063–1067.

    CAS  PubMed  Google Scholar 

  144. Okano, M., S. Xie, and E. Li. 1998. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genetics 19: 219–220.

    Article  CAS  PubMed  Google Scholar 

  145. Okano, M., D.W. Bell, D.A. Haber, and E. Li. 1999. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257.

    Article  CAS  PubMed  Google Scholar 

  146. Ott, M., and E. Verdin. 2010. HAT trick: p300, small molecule, inhibitor. Chemistry & Biology 17: 417–418.

    Article  CAS  Google Scholar 

  147. Pachaiyappan, B., and P.M. Woster. 2014. Design of small molecule epigenetic modulators. Bioorganic & Medicinal Chemistry Letters 24: 21–32.

    Article  CAS  Google Scholar 

  148. Peng, L., Z. Xu, Z. Liu, Y. Wei, H. Sun, Z. Li, X. Zhao, and C. Gao. 2015. An iron-based green approach to 1-h production of single-layer graphene oxide. Nature Communications 6: 5716.

    Article  CAS  PubMed  Google Scholar 

  149. Perez-Salvia, M., and M. Esteller. 2017. Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics 12: 323–339.

    Article  PubMed  Google Scholar 

  150. Peserico, A., and C. Simone. 2011. Physical and functional HAT/HDAC interplay regulates protein acetylation balance. Journal of Biomedicine & Biotechnology 2011: 371832.

    Article  CAS  Google Scholar 

  151. Picaud, S., C. Wells, I. Felletar, D. Brotherton, S. Martin, P. Savitsky, B. Diez-Dacal, M. Philpott, C. Bountra, H. Lingard, O. Fedorov, S. Muller, P.E. Brennan, S. Knapp, and P. Filippakopoulos. 2013. RVX- 208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proceedings of the National Academy of Sciences of the United States of America 110: 19754–19759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Prusevich, P., J.H. Kalin, S.A. Ming, M. Basso, J. Givens, X. Li, J. Hu, M.S. Taylor, A.M. Cieniewicz, P.Y. Hsiao, R. Huang, H. Roberson, N. Adejola, L.B. Avery, R.A. Casero Jr., S.D. Taverna, J. Qian, A.J. Tackett, R.R. Ratan, O.G. Mcdonald, A.P. Feinberg, and P.A. Cole. 2014. A selective phenelzine analogue inhibitor of histone demethylase LSD1. ACS Chemical Biology 9: 1284–1293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Qi, W., H. Chan, L. Teng, L. Li, S. Chuai, R. Zhang, J. Zeng, M. Li, H. Fan, Y. Lin, J. Gu, O. Ardayfio, J.H. Zhang, X. Yan, J. Fang, Y. Mi, M. Zhang, T. Zhou, G. Feng, Z. Chen, G. Li, T. Yang, K. Zhao, X. Liu, Z. Yu, C.X. Lu, P. Atadja, and E. Li. 2012. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proceedings of the National Academy of Sciences of the United States of America 109: 21360–21365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Qin, W., P. Wolf, N. Liu, S. Link, M. Smets, F. La Mastra, I. Forne, G. Pichler, D. Horl, K. Fellinger, F. Spada, I.M. Bonapace, A. Imhof, H. Harz, and H. Leonhardt. 2015. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Research 25: 911–929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Ramakrishnan, V. 1997. Histone structure and the organization of the nucleosome. Annual Review of Biophysics and Biomolecular Structure 26: 83–112.

    Article  CAS  PubMed  Google Scholar 

  156. Ren, J., B.N. Singh, Q. Huang, Z. Li, Y. Gao, P. Mishra, Y.L. Hwa, J. Li, S.C. Dowdy, and S.W. Jiang. 2011. DNA hypermethylation as a chemotherapy target. Cellular Signalling 23: 1082–1093.

    Article  CAS  PubMed  Google Scholar 

  157. Ren, C., K. Morohashi, A.N. Plotnikov, J. Jakoncic, S.G. Smith, J. Li, L. Zeng, Y. Rodriguez, V. Stojanoff, M. Walsh, and M.M. Zhou. 2015. Small- molecule modulators of methyl-lysine binding for the CBX7 chromodomain. Chemistry & Biology 22: 161–168.

    Article  CAS  Google Scholar 

  158. Rhee, I., K.E. Bachman, B.H. Park, K.W. Jair, R.W. Yen, K.E. Schuebel, H. Cui, A.P. Feinberg, C. Lengauer, K.W. Kinzler, S.B. Baylin, and B. Vogelstein. 2002. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416: 552–556.

    Article  CAS  PubMed  Google Scholar 

  159. Richon, V.M., S. Emiliani, E. Verdin, Y. Webb, R. Breslow, R.A. Rifkind, and P.A. Marks. 1998. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proceedings of the National Academy of Sciences of the United States of America 95: 3003–3007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Richter, C., K. Oktaba, J. Steinmann, J. Muller, and J.A. Knoblich. 2011. The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements. Nature Cell Biology 13: 1029–1039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Rilova, E., A. Erdmann, C. Gros, V. Masson, Y. Aussagues, V. Poughon-Cassabois, A. Rajavelu, A. Jeltsch, Y. Menon, N. Novosad, J.M. Gregoire, S. Vispe, P. Schambel, F. Ausseil, F. Sautel, P.B. Arimondo, and F. Cantagrel. 2014. Design, synthesis and biological evaluation of 4-amino-N- (4-aminophenyl)benzamide analogues of quinoline-based SGI- 1027 as inhibitors of DNA methylation. ChemMedChem 9: 590–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rodriguez-Paredes, M., and M. Esteller. 2011. Cancer epigenetics reaches mainstream oncology. Nature Medicine 17: 330–339.

    Article  CAS  PubMed  Google Scholar 

  163. Rose, N.R., S.S. Ng, J. Mecinovic, B.M. Lienard, S.H. Bello, Z. Sun, M.A. Mcdonough, U. Oppermann, and C.J. Schofield. 2008. Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. Journal of Medicinal Chemistry 51: 7053–7056.

    Article  CAS  PubMed  Google Scholar 

  164. Rosenfeld, J.A., Z. Wang, D.E. Schones, K. Zhao, R. Desalle, and M.Q. Zhang. 2009. Determination of enriched histone modifications in non-genic portions of the human genome. BMC Genomics 10: 143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Ruthenburg, A.J., C.D. Allis, and J. Wysocka. 2007. Methylation of lysine 4 on histone H3: Intricacy of writing and reading a single epigenetic mark. Molecular Cell 25: 15–30.

    Article  CAS  PubMed  Google Scholar 

  166. Sanchez, R., and M.M. Zhou. 2009. The role of human bromodomains in chromatin biology and gene transcription. Current Opinion in Drug Discovery & Development 12: 659–665.

    CAS  Google Scholar 

  167. Santi, D.V., A. Norment, and C.E. Garrett. 1984. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proceedings of the National Academy of Sciences of the United States of America 81: 6993–6997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sarkisjan, D., J.R. Julsing, K. Smid, D. de Klerk, A.B. van Kuilenburg, R. Meinsma, Y.B. Lee, D.J. Kim, and G.J. Peters. 2016. The cytidine analog fluorocyclopentenylcytosine (RX-3117) is activated by uridine-cytidine kinase 2. PLoS One 11: e0162901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Savickiene, J., G. Treigyte, A. Jazdauskaite, V.V. Borutinskaite, and R. Navakauskiene. 2012. DNA methyltransferase inhibitor RG108 and histone deacetylase inhibitors cooperate to enhance NB4 cell differentiation and E-cadherin re- expression by chromatin remodelling. Cell Biology International 36: 1067–1078.

    Article  CAS  PubMed  Google Scholar 

  170. Schlesinger, Y., R. Straussman, I. Keshet, S. Farkash, M. Hecht, J. Zimmerman, E. Eden, Z. Yakhini, E. Ben-Shushan, B.E. Reubinoff, Y. Bergman, I. Simon, and H. Cedar. 2007. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nature Genetics 39: 232–236.

    Article  CAS  PubMed  Google Scholar 

  171. Segura-Pacheco, B., C. Trejo-Becerril, E. Perez-Cardenas, L. Taja-Chayeb, I. Mariscal, A. Chavez, C. Acuna, A.M. Salazar, M. Lizano, and A. Duenas-Gonzalez. 2003. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clinical Cancer Research 9: 1596–1603.

    CAS  PubMed  Google Scholar 

  172. Seto, E., and M. Yoshida. 2014. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harbor Perspectives in Biology 6: a018713.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Shi, Y. 2007. Histone lysine demethylases: Emerging roles in development, physiology and disease. Nature Reviews. Genetics 8: 829–833.

    Article  CAS  PubMed  Google Scholar 

  174. Siu, K.T., H. Eda, L. Santo, J. Ramachandran, M. Koulnis, J. Mertz, R.J. Sims, M. Cooper, and N.S. Raje. 2015. Effect of the BET inhibitor, Cpi-0610, alone and in combination with lenalidomide in multiple myeloma. Blood 126 (23): 4255.

    Article  Google Scholar 

  175. Song, S.H., S.W. Han, and Y.J. Bang. 2011. Epigenetic-based therapies in cancer: Progress to date. Drugs 71: 2391–2403.

    Article  CAS  PubMed  Google Scholar 

  176. Sproul, D., N. Gilbert, and W.A. Bickmore. 2005. The role of chromatin structure in regulating the expression of clustered genes. Nature Reviews. Genetics 6: 775–781.

    Article  CAS  PubMed  Google Scholar 

  177. Srinivasan, P.R., and E. Borek. 1964. Species variation of the RNA methylases. Biochemistry 3: 616–619.

    Article  CAS  PubMed  Google Scholar 

  178. Steger, D.J., M.I. Lefterova, L. Ying, A.J. Stonestrom, M. Schupp, D. Zhuo, A.L. Vakoc, J.E. Kim, J. Chen, M.A. Lazar, G.A. Blobel, and C.R. Vakoc. 2008. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Molecular and Cellular Biology 28: 2825–2839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Stimson, L., M.G. Rowlands, Y.M. Newbatt, N.F. Smith, F.I. Raynaud, P. Rogers, V. Bavetsias, S. Gorsuch, M. Jarman, A. Bannister, T. Kouzarides, E. Mcdonald, P. Workman, and G.W. Aherne. 2005. Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Molecular Cancer Therapeutics 4: 1521–1532.

    Article  CAS  PubMed  Google Scholar 

  180. Stubbs, M., R. Collins, A. Volgina, M.K. Liu, M. Favata, M. Rupar, X. Wen, R. Sparks, T. Maduskuie, M. Covington, T. Burn, B. Ruggeri, A.P. Combs, W.Q. Yao, R. Huber, G. Hollis, P. Scherle, and P.C.C. Liu. 2016. Activity of the BET inhibitor INCB054329 in models of lymphoma. Cancer Research 76.

    Google Scholar 

  181. Suraweera, A., K.J. O’Byrne, and D.J. Richard. 2018. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Frontiers in Oncology 8: 92.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Suzuki, T., M.N. Khan, H. Sawada, E. Imai, Y. Itoh, K. Yamatsuta, N. Tokuda, J. Takeuchi, T. Seko, H. Nakagawa, and N. Miyata. 2012. Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors. Journal of Medicinal Chemistry 55: 5760–5773.

    Article  CAS  PubMed  Google Scholar 

  183. Tahiliani, M., K.P. Koh, Y. Shen, W.A. Pastor, H. Bandukwala, Y. Brudno, S. Agarwal, L.M. Iyer, D.R. Liu, L. Aravind, and A. Rao. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324: 930–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Tan, J., X. Yang, L. Zhuang, X. Jiang, W. Chen, P.L. Lee, R.K. Karuturi, P.B. Tan, E.T. Liu, and Q. Yu. 2007. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes & Development 21: 1050–1063.

    Article  CAS  Google Scholar 

  185. Tanabe, K., J. Liu, D. Kato, H. Kurumizaka, K. Yamatsugu, M. Kanai, and S.A. Kawashima. 2018. LC-MS/MS-based quantitative study of the acyl group- and site-selectivity of human sirtuins to acylated nucleosomes. Scientific Reports 8: 2656.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Teske, K.A., and M.K. Hadden. 2017. Methyllysine binding domains: Structural insight and small molecule probe development. European Journal of Medicinal Chemistry 136: 14–35.

    Article  CAS  PubMed  Google Scholar 

  187. Theodoulou, N.H., P. Bamborough, A.J. Bannister, I. Becher, R.A. Bit, K.H. Che, C.W. Chung, A. Dittmann, G. Drewes, D.H. Drewry, L. Gordon, P. Grandi, M. Leveridge, M. Lindon, A.M. Michon, J. Molnar, S.C. Robson, N.C. Tomkinson, T. Kouzarides, R.K. Prinjha, and P.G. Humphreys. 2016. Discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition. Journal of Medicinal Chemistry 59: 1425–1439.

    Article  CAS  PubMed  Google Scholar 

  188. Thottassery, J.V., V. Sambandam, P.W. Allan, J.A. Maddry, Y.Y. Maxuitenko, K. Tiwari, M. Hollingshead, and W.B. Parker. 2014. Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4′-thio-2′-deoxycytidine and 5-aza-4′-thio-2′-deoxycytidine. Cancer Chemotherapy and Pharmacology 74: 291–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Tian, X., S. Zhang, H.M. Liu, Y.B. Zhang, C.A. Blair, D. Mercola, P. Sassone-Corsi, and X. Zi. 2013. Histone lysine-specific methyltransferases and demethylases in carcinogenesis: New targets for cancer therapy and prevention. Current Cancer Drug Targets 13: 558–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Tokarz, P., K. Kaarniranta, and J. Blasiak. 2016. Inhibition of DNA methyltransferase or histone deacetylase protects retinal pigment epithelial cells from DNA damage induced by oxidative stress by the stimulation of antioxidant enzymes. European Journal of Pharmacology 776: 167–175.

    Article  CAS  PubMed  Google Scholar 

  191. Tsai, H.C., H. Li, L. Van Neste, Y. Cai, C. Robert, F.V. Rassool, J.J. Shin, K.M. Harbom, R. Beaty, E. Pappou, J. Harris, R.W. Yen, N. Ahuja, M.V. Brock, V. Stearns, D. Feller-Kopman, L.B. Yarmus, Y.C. Lin, A.L. Welm, J.P. Issa, I. Minn, W. Matsui, Y.Y. Jang, S.J. Sharkis, S.B. Baylin, and C.A. Zahnow. 2012. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21: 430–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Unoki, M., T. Nishidate, and Y. Nakamura. 2004. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23: 7601–7610.

    Article  CAS  PubMed  Google Scholar 

  193. Van Haaften, G., G.L. Dalgliesh, H. Davies, L. Chen, G. Bignell, C. Greenman, S. Edkins, C. Hardy, S. O’Meara, J. Teague, A. Butler, J. Hinton, C. Latimer, J. Andrews, S. Barthorpe, D. Beare, G. Buck, P.J. Campbell, J. Cole, S. Forbes, M. Jia, D. Jones, C.Y. Kok, C. Leroy, M.L. Lin, D.J. Mcbride, M. Maddison, S. Maquire, K. Mclay, A. Menzies, T. Mironenko, L. Mulderrig, L. Mudie, E. Pleasance, R. Shepherd, R. Smith, L. Stebbings, P. Stephens, G. Tang, P.S. Tarpey, R. Turner, K. Turrell, J. Varian, S. West, S. Widaa, P. Wray, V.P. Collins, K. Ichimura, S. Law, J. Wong, S.T. Yuen, S.Y. Leung, G. Tonon, R.A. Depinho, Y.T. Tai, K.C. Anderson, R.J. Kahnoski, A. Massie, S.K. Khoo, B.T. Teh, M.R. Stratton, and P.A. Futreal. 2009. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genetics 41: 521–523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Vaswani, R.G., V.S. Gehling, L.A. Dakin, A.S. Cook, C.G. Nasveschuk, M. Duplessis, P. Iyer, S. Balasubramanian, F. Zhao, A.C. Good, R. Campbell, C. Lee, N. Cantone, R.T. Cummings, E. Normant, S.F. Bellon, B.K. Albrecht, J.C. Harmange, P. Trojer, J.E. Audia, Y. Zhang, N. Justin, S. Chen, J.R. Wilson, and S.J. Gamblin. 2016. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2- methyl-1-(1-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI- 1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. Journal of Medicinal Chemistry 59: 9928–9941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Venugopal, B., R. Baird, R.S. Kristeleit, R. Plummer, R. Cowan, A. Stewart, N. Fourneau, P. Hellemans, Y. Elsayed, S. Mcclue, J.W. Smit, A. Forslund, C. Phelps, J. Camm, T.R. Evans, J.S. DE Bono, and U. Banerji. 2013. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clinical Cancer Research 19: 4262–4272.

    Article  CAS  PubMed  Google Scholar 

  196. Vigushin, D.M., S. Ali, P.E. Pace, N. Mirsaidi, K. Ito, I. Adcock, and R.C. Coombes. 2001. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clinical Cancer Research 7: 971–976.

    CAS  PubMed  Google Scholar 

  197. Villar-Garea, A., M.F. Fraga, J. Espada, and M. Esteller. 2003. Procaine is a DNA- demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Research 63: 4984–4989.

    CAS  PubMed  Google Scholar 

  198. Von Tresckow, B., C. Sayehli, W.E. Aulitzky, M.E. Goebeler, M. Schwab, E. Braz, B. Krauss, R. Krauss, F. Hermann, R. Bartz, and A. Engert. 2018. Phase I study of domatinostat (4SC-202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies. European Journal of Haematology 102 (2): 163–173.

    Article  CAS  Google Scholar 

  199. Wagner, E.K., N. Nath, R. Flemming, J.B. Feltenberger, and J.M. Denu. 2012. Identification and characterization of small molecule inhibitors of a plant homeodomain finger. Biochemistry 51: 8293–8306.

    Article  CAS  PubMed  Google Scholar 

  200. Wang, Y., J. Wysocka, J. Sayegh, Y.H. Lee, J.R. Perlin, L. Leonelli, L.S. Sonbuchner, C.H. Mcdonald, R.G. Cook, Y. Dou, R.G. Roeder, S. Clarke, M.R. Stallcup, C.D. Allis, and S.A. Coonrod. 2004. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306: 279–283.

    Article  CAS  PubMed  Google Scholar 

  201. Wang, M., X. Liu, J. Guo, X. Weng, G. Jiang, Z. Wang, and L. He. 2015. Inhibition of LSD1 by Pargyline inhibited process of EMT and delayed progression of prostate cancer in vivo. Biochemical and Biophysical Research Communications 467: 310–315.

    Article  CAS  PubMed  Google Scholar 

  202. Wang, Y., J. He, M. Liao, M. Hu, W. Li, H. Ouyang, X. Wang, T. Ye, Y. Zhang, and L. Ouyang. 2019. An overview of Sirtuins as potential therapeutic target: Structure, function and modulators. European Journal of Medicinal Chemistry 161: 48–77.

    Article  CAS  PubMed  Google Scholar 

  203. Wapenaar, H., and F.J. Dekker. 2016. Histone acetyltransferases: Challenges in targeting bi-substrate enzymes. Clinical Epigenetics 8: 59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Waters, N.J., S.R. Daigle, B.N. Rehlaender, A. Basavapathruni, C.T. Campbell, T.B. Jensen, B.F. Truitt, E.J. Olhava, R.M. Pollock, K.A. Stickland, and A. Dovletoglou. 2015. Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target. Journal of Controlled Release 220: 758–765.

    Article  CAS  PubMed  Google Scholar 

  205. Widschwendter, M., H. Fiegl, D. Egle, E. Mueller-Holzner, G. Spizzo, C. Marth, D.J. Weisenberger, M. Campan, J. Young, I. Jacobs, and P.W. Laird. 2007. Epigenetic stem cell signature in cancer. Nature Genetics 39: 157–158.

    Article  CAS  PubMed  Google Scholar 

  206. Willmann, D., S. Lim, S. Wetzel, E. Metzger, A. Jandausch, W. Wilk, M. Jung, I. Forne, A. Imhof, A. Janzer, J. Kirfel, H. Waldmann, R. Schule, and R. Buettner. 2012. Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor. International Journal of Cancer 131: 2704–2709.

    Article  CAS  PubMed  Google Scholar 

  207. Wilting, R.H., and J.H. Dannenberg. 2012. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resistance Updates 15: 21–38.

    Article  CAS  PubMed  Google Scholar 

  208. Wolf, S.S. 2009. The protein arginine methyltransferase family: An update about function, new perspectives and the physiological role in humans. Cellular and Molecular Life Sciences 66: 2109–2121.

    Article  CAS  PubMed  Google Scholar 

  209. Wyhs, N., D. Walker, H. Giovinazzo, S. Yegnasubramanian, and W.G. Nelson. 2014. Time-resolved fluorescence resonance energy transfer assay for discovery of small-molecule inhibitors of methyl-CpG binding domain protein 2. Journal of Biomolecular Screening 19: 1060–1069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Xu, Y., and C.R. Vakoc. 2017. Targeting cancer cells with BET bromodomain inhibitors. Cold Spring Harbor Perspectives in Medicine 7 (7).

    Google Scholar 

  211. Xu, T., S.S. Park, B.D. Giaimo, D. Hall, F. Ferrante, D.M. Ho, K. Hori, L. Anhezini, I. Ertl, M. Bartkuhn, H. Zhang, E. Milon, K. Ha, K.P. Conlon, R. Kuick, B. Govindarajoo, Y. Zhang, Y. Sun, Y. Dou, V. Basrur, K.S. Elenitoba-Johnson, A.I. Nesvizhskii, J. Ceron, C.Y. Lee, T. Borggrefe, R.A. Kovall, and J.F. Rual. 2017. RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1. The EMBO Journal 36: 3232–3249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Yan, L., C. Yan, K. Qian, H. Su, S.A. Kofsky-Wofford, W.C. Lee, X. Zhao, M.C. Ho, I. Ivanov, and Y.G. Zheng. 2014. Diamidine compounds for selective inhibition of protein arginine methyltransferase 1. Journal of Medicinal Chemistry 57: 2611–2622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Yee, A.J., and N.S. Raje. 2018. Panobinostat and multiple myeloma in 2018. The Oncologist 23: 516–517.

    Article  PubMed  PubMed Central  Google Scholar 

  214. Yiannakopoulou, E.C. 2015. Targeting DNA methylation with green tea catechins. Pharmacology 95: 111–116.

    Article  CAS  PubMed  Google Scholar 

  215. Yoo, C.B., S. Jeong, G. Egger, G. Liang, P. Phiasivongsa, C. Tang, S. Redkar, and P.A. Jones. 2007. Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Research 67: 6400–6408.

    Article  CAS  PubMed  Google Scholar 

  216. Yoon, J.H., L.E. Smith, Z. Feng, M. Tang, C.S. Lee, and G.P. Pfeifer. 2001. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: Similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Research 61: 7110–7117.

    CAS  PubMed  Google Scholar 

  217. Yoshida, M., M. Kijima, M. Akita, and T. Beppu. 1990. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. The Journal of Biological Chemistry 265: 17174–17179.

    CAS  PubMed  Google Scholar 

  218. Yoshida, M., N. Kudo, S. Kosono, and A. Ito. 2017. Chemical and structural biology of protein lysine deacetylases. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 93: 297–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Younes, A., Y. Oki, R.G. Bociek, J. Kuruvilla, M. Fanale, S. Neelapu, A. Copeland, D. Buglio, A. Galal, J. Besterman, Z. Li, M. Drouin, T. Patterson, M.R. Ward, J.K. Paulus, Y. Ji, L.J. Medeiros, and R.E. Martell. 2011. Mocetinostat for relapsed classical Hodgkin’s lymphoma: An open-label, single-arm, phase 2 trial. The Lancet Oncology 12: 1222–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Zhang, J., S. Zhang, Y. Wang, H. Cheng, L. Hao, Y. Zhai, Z. Zhang, X. An, X. Ma, X. Zhang, Z. Li, and B. Tang. 2017. Effect of TET inhibitor on bovine parthenogenetic embryo development. PLoS One 12: e0189542.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Zhang, D., A.S. Leal, S. Carapellucci, K. Zydeck, M.B. Sporn, and K.T. Liby. 2018. Chemoprevention of preclinical breast and lung cancer with the bromodomain inhibitor I-BET 762. Cancer Prevention Research (Philadelphia, Pa.) 11: 143–156.

    Article  CAS  Google Scholar 

  222. Zhao, Y., C.Y. Yang, and S. Wang. 2013. The making of I-BET762, a BET bromodomain inhibitor now in clinical development. Journal of Medicinal Chemistry 56: 7498–7500.

    Article  CAS  PubMed  Google Scholar 

  223. Zheng, Y.C., B. Yu, G.Z. Jiang, X.J. Feng, P.X. He, X.Y. Chu, W. Zhao, and H.M. Liu. 2016. Irreversible LSD1 inhibitors: Application of tranylcypromine and its derivatives in cancer treatment. Current Topics in Medicinal Chemistry 16: 2179–2188.

    Article  CAS  PubMed  Google Scholar 

  224. Zhu, Q.S., Y. Huang, L.J. Marton, P.M. Woster, N.E. Davidson, and R.A. Casero. 2012. Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells. Amino Acids 42: 887–898.

    Article  CAS  PubMed  Google Scholar 

  225. Zurita-Lopez, C.I., T. Sandberg, R. Kelly, and S.G. Clarke. 2012. Human protein arginine methyltransferase 7 (PRMT7) is a type III enzyme forming omega-NG- monomethylated arginine residues. The Journal of Biological Chemistry 287: 7859–7870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Central Research Institute of Fukuoka University (Grant No. 186005 to T.K.). We thank Edanz (www.edanzediting.co.jp) for editing the English text of a draft of this manuscript.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

    Tomohiro Kozako & Shin-ichiro Honda

  2. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yukihiro Itoh & Takayoshi Suzuki

  3. CREST, Japan Science and Technology Agency (JST), Saitama, Japan

    Takayoshi Suzuki

Authors
  1. Tomohiro Kozako
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukihiro Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shin-ichiro Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takayoshi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomohiro Kozako .

Editor information

Editors and Affiliations

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Mariano Bizzarri

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kozako, T., Itoh, Y., Honda, Si., Suzuki, T. (2020). Epigenetic Control Using Small Molecules in Cancer. In: Bizzarri, M. (eds) Approaching Complex Diseases. Human Perspectives in Health Sciences and Technology, vol 2. Springer, Cham. https://doi.org/10.1007/978-3-030-32857-3_6

Download citation

Publish with us

Policies and ethics

Search

Navigation