Abstract
Gene expression is regulated and tightly controlled by epigenetic mechanisms. Alterations of these mechanisms are frequently observed in various diseases, particularly, in various types of cancer. Malignant transformation is caused by the impairment of the mechanisms of cell differentiation and cell cycle control associated with epigenetic changes. Altered patterns of epigenetic modification associated with malignancies can potentially be reversed by some agents that act on the key proteins responsible for DNA/histone modification and chromatin remodelling. Examples of such substances include the inhibitors of DNA methyltransferases or histone deacetylase. During the recent years, a number of such substances have been evaluated as potential therapeutic agents against certain types of cancer in preclinical and clinical studies, and some of them have been approved for treatment of hematological cancers. Application of epidrugs for therapy of solid tumors remains, however, more challenging. In this review, we summarize the current knowledge on the most studied mechanisms of epigenetic modification and the available epigenetically active drugs.
Keywords: Epigenetics, cancer, acetylation, methylation, DNMT inhibitors, HDAC inhibitors.
[1]
Roth TL. Epigenetics of neurobiology and behavior during development and adulthood. Dev Psychobiol 2012; 54(6): 590-7.
[2]
Zhao M, Wang Z, Yung S, Lu Q. Epigenetic dynamics in immunity and autoimmunity. Int J Biochem Cell Biol 2015; 67: 65-74.
[3]
Farooqi AA, Tang JY, Li RN, et al. Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers. Int J Nanomedicine 2015; 10: 3183-91.
[4]
Chun P. Histone deacetylase inhibitors in hematological malignancies and solid tumors. Arch Pharm Res 2015; 38(6): 933-49.
[5]
Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immuneoncology. Nat Rev Cancer 2019; 19(3): 151-61.
[6]
Molife LR, Attard G, Fong PC, et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Ann Oncol 2010; 21(1): 109-13.
[7]
Balch C, Nephew KP. Epigenetic targeting therapies to overcome chemotherapy resistance. Adv Exp Med Biol 2013; 754: 285-311.
[8]
Kaminskas E, Farrell A, Abraham S, et al. Approval summary: Azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005; 11(10): 3604-8.
[11]
Campas-Moya C. Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today (Barc) 2009; 45: 787-95.
[12]
Richardson PG, Harvey RD, Laubach JP, Moreau P, Lonial S, San-Miguel JF. Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. Expert Rev Clin Pharmacol 2016; 9(1): 35-48.
[14]
Serman A, Vlahović M, Serman L, Bulić-Jakus F. DNA methylation as a regulatory mechanism for gene expression in mammals. Coll Antropol 2006; 30: 665-71. PLoS One 2012; 7(1)e30815
[15]
Hermann A, Gowher H, Jeltsch A. Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci 2004; 61(19-20): 2571-87.
[16]
Gao Q, Steine EJ, Barrasa MI, et al. Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression. Proc Natl Acad Sci USA 2011; 108(44): 18061-6.
[17]
Linhart HG, Lin H, Yamada Y, et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 2007; 21(23): 3110-22.
[18]
Nosho K, Shima K, Irahara N, et al. DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin Cancer Res 2009; 15(11): 3663-71.
[19]
Ito S, Shen L, Dai Q, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011; 333(6047): 1300-3.
[20]
Wen L, Tang F. Genomic distribution and possible functions of DNA hydroxymethylation in the brain. Genomics 2014; 104(5): 341-6.
[21]
Han JA, An J, Ko M. Functions of TET proteins in hematopoietic transformation. Mol Cells 2015; 38(11): 925-35.
[23]
Wang R, Xin M, Li Y, Zhang P, Zhang M. The functions of histone modification enzymes in cancer. Curr Protein Pept Sci 2016; 17(5): 438-45.
[25]
Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129(4): 823-37.
[26]
Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell 2007; 128(4): 707-19.
[27]
Chen P, Wang Y, Li G. Dynamics of histone variant H3.3 and its coregulation with H2A.Z at enhancers and promoters. Nucleus 2014; 5(1): 21-7.
[28]
Radman-Livaja M, Rando OJ. Nucleosome positioning: how is it established, and why does it matter? Dev Biol 2010; 339(2): 258-66.
[29]
Wen B, Wu H, Loh YH, Briem E, Daley GQ, Feinberg AP. Euchromatin islands in large heterochromatin domains are enriched for CTCF binding and differentially DNA-methylated regions. BMC Genomics 2012; 13: 566.
[30]
Fujimura Y, Isono K, Vidal M, et al. Distinct roles of Polycomb group gene products in transcriptionally repressed and active domains of Hoxb8. Development 2006; 133(12): 2371-81.
[31]
Asangani IA, Ateeq B, Cao Q, et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol Cell 2013; 49(1): 80-93.
[32]
Rinn JL, Kertesz M, Wang JK, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007; 129(7): 1311-23.
[33]
Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010; 464(7291): 1071-6.
[35]
Hatziapostolou M, Iliopoulos D. Epigenetic aberrations during oncogenesis. Cell Mol Life Sci 2011; 68(10): 1681-702.
[36]
Yoshioka K, Atsumi Y, Nakagama H, Teraoka H. Development of cancer-initiating cells and immortalized cells with genomic instability. World J Stem Cells 2015; 7(2): 483-9.
[37]
Hsieh YH, Hsu JL, Su IJ, Huang W. Genomic instability caused by hepatitis B virus: into the hepatoma inferno. Front Biosci 2011; 16: 2586-97.
[38]
Venkatesan S, Natarajan AT, Hande MP. Chromosomal instability--mechanisms and consequences. Mutat Res Genet Toxicol Environ Mutagen 2015; 793: 176-84.
[39]
Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005; 37(4): 391-400.
[40]
Tryndyak VP, Kovalchuk O, Pogribny IP. Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins. Cancer Biol Ther 2006; 5(1): 65-70.
[41]
You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 2012; 22(1): 9-20.
[42]
Tie R, Zhang T, Fu H, et al. Association between DNMT3A mutations and prognosis of adults with de novo acute myeloid leukemia: A systematic review and meta-analysis. PLoS One 2014; 9(6)e93353
[43]
Van der Meulen J, Speleman F, Van Vlierberghe P. The H3K27me3 demethylase UTX in normal development and disease. Epigenetics 2014; 9(5): 658-68.
[44]
Kazanets A, Shorstova T, Hilmi K, Marques M, Witcher M. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. Biochim Biophys Acta 2016; 1865(2): 275-88.
[45]
Clark SJ. Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis. Hum Mol Genet 2007; 16(Spec No 1): R88-95.
[46]
Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18(6): 553-67.
[47]
Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483(7390): 479-83.
[48]
Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360(22): 2289-301.
[49]
Coe BP, Thu KL, Aviel-Ronen S, et al. Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer. PLoS One 2013; 8(8)e71670
[50]
Sekine I, Minna JD, Nishio K, Saijo N, Tamura T. Genes regulating the sensitivity of solid tumor cell lines to cytotoxic agents: A literature review. Jpn J Clin Oncol 2007; 37(5): 329-36.
[51]
Shia J. Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma. Semin Diagn Pathol 2015; 32(5): 352-61.
[52]
Gao D, Herman JG, Guo M. The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer. Oncotarget 2016; 7(24): 37331-46.
[53]
Baylin SB, Ohm JE. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006; 6(2): 107-16.
[54]
Ferguson LR, Tatham AL, Lin Z, Denny WA. Epigenetic regulation of gene expression as an anticancer drug target. Curr Cancer Drug Targets 2011; 11(2): 199-212.
[55]
Mossman D, Kim KT, Scott RJ. Demethylation by 5-aza-2′-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists. BMC Cancer 2010; 10: 366.
[56]
Mossman D, Scott RJ. Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation. PLoS One 2011; 6(8)e23127
[57]
Estey EH. Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 2013; 27(9): 1803-12.
[58]
Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA 2010; 107(16): 7473-8.
[59]
Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 2010; 28(4): 556-61.
[60]
Lübbert M, Rüter BH, Claus R, et al. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica 2012; 97(3): 393-401.
[61]
Yoo CB, Jeong S, Egger G, et al. Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 2007; 67(13): 6400-8.
[62]
Chuang JC, Warner SL, Vollmer D, et al. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther 2010; 9(5): 1443-50.
[63]
Hummel-Eisenbeiss J, Hascher A, Hals PA, et al. The role of human equilibrative nucleoside transporter 1 on the cellular transport of the DNA methyltransferase inhibitors 5-azacytidine and CP-4200 in human leukemia cells. Mol Pharmacol 2013; 84(3): 438-50.
[64]
Brueckner B, Rius M, Markelova MR, et al. Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol Cancer Ther 2010; 9(5): 1256-64.
[65]
Tanaka H, Marumo H, Nagai T, Okada M, Taniguchi K. Nanaomycins, new antibiotics produced by a strain of Streptomyces. III. A new component, nanaomycin C, and biological activities of nanaomycin derivatives. J Antibiot (Tokyo) 1975; 28(12): 925-30.
[66]
Kuck D, Singh N, Lyko F, Medina-Franco JL. Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation. Bioorg Med Chem 2010; 18(2): 822-9.
[67]
Kuck D, Caulfield T, Lyko F, Medina-Franco JL. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Mol Cancer Ther 2010; 9(11): 3015-23.
[68]
Kollar J, Frecer V. Selective inhibitors of zinc-dependent histone deacetylases. Therapeutic targets relevant to cancer. Curr Pharm Des 2015; 21(11): 1472-502.
[69]
Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 2007; 26(37): 5489-504.
[70]
Federico M, Bagella L. Histone deacetylase inhibitors in the treatment of hematological malignancies and solid tumors. J Biomed Biotechnol 2011; 2011475641
[71]
Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007; 109(1): 31-9.
[72]
Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007; 25(21): 3109-15.
[73]
Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009; 27(32): 5410-7.
[74]
Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010; 28(29): 4485-91.
[75]
Khot A, Dickinson M, Prince HM. Panobinostat in lymphoid and myeloid malignancies. Expert Opin Investig Drugs 2013; 22(9): 1211-23.
[76]
Li X, Zhang J, Xie Y, Jiang Y, Yingjie Z, Xu W. Progress of HDAC inhibitor panobinostat in the treatment of cancer. Curr Drug Targets 2014; 15(6): 622-34.
[77]
Knipstein J, Gore L. Entinostat for treatment of solid tumors and hematologic malignancies. Expert Opin Investig Drugs 2011; 20(10): 1455-67.
[78]
Shen L, Ciesielski M, Ramakrishnan S, et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One 2012; 7(1)e30815
[79]
Saji S, Kimura-Tsuchiya R. Combination of molecular-targeted drugs with endocrine therapy for hormone-resistant breast cancer. Int J Clin Oncol 2015; 20(2): 268-72.
[80]
Ruiz R, Raez LE, Rolfo C. Entinostat (SNDX-275) for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs 2015; 24(8): 1101-9.
[81]
Le Tourneau C, Siu LL. Promising antitumor activity with MGCD0103, a novel isotype-selective histone deacetylase inhibitor. Expert Opin Investig Drugs 2008; 17(8): 1247-54.
[82]
Younes A, Oki Y, Bociek RG, et al. Mocetinostat for relapsed classical Hodgkin’s lymphoma: An open-label, single-arm, phase 2 trial. Lancet Oncol 2011; 12(13): 1222-8.
[83]
Boumber Y, Younes A, Garcia-Manero G. Mocetinostat (MGCD0103): A review of an isotype-specific histone deacetylase inhibitor. Expert Opin Investig Drugs 2011; 20(6): 823-9.
[84]
Di Cerbo V, Schneider R. Cancers with wrong HATs: The impact of acetylation. Brief Funct Genomics 2013; 12(3): 231-43.
[85]
Balasubramanyam K, Varier RA, Altaf M, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 2004; 279(49): 51163-71.
[86]
Sun Y, Jiang X, Chen S, Price BD. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. FEBS Lett 2006; 580(18): 4353-6.
[87]
Prasad S, Ravindran J, Sung B, Pandey MK, Aggarwal BB. Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins. Mol Cancer Ther 2010; 9(4): 856-68.
[88]
Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010; 501(1): 79-90.
[89]
Hasima N, Aggarwal BB. Targeting proteasomal pathways by dietary curcumin for cancer prevention and treatment. Curr Med Chem 2014; 21(14): 1583-94.
[90]
Ntranos A, Casaccia P. Bromodomains: Translating the words of lysine acetylation into myelin injury and repair. Neurosci Lett 2016; 625: 4-10.
[91]
Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer 2012; 12(7): 465-77.
[92]
LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell 2008; 30(1): 51-60.
[93]
Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol 2008; 28(3): 967-76.
[94]
Sengupta D, Kannan A, Kern M, et al. Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma. Epigenetics 2015; 10(6): 460-6.
[96]
Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget 2015; 6(8): 5501-16.
[97]
Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature 2010; 468(7327): 1067-73.
[98]
Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010; 468(7327): 1119-23.
[99]
Zhao Y, Yang CY, Wang S. The making of I-BET762, a BET bromodomain inhibitor now in clinical development. J Med Chem 2013; 56: 7498-500.
[100]
Blumenschein GR Jr, Kies MS, Papadimitrakopoulou VA, et al. Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs 2008; 26(1): 81-7.
[101]
Vansteenkiste J, Van Cutsem E, Dumez H, et al. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs 2008; 26(5): 483-8.
[102]
Bradley D, Rathkopf D, Dunn R, et al. Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium. Cancer 2009; 115(23): 5541-9.
[103]
Rathkopf DE, Picus J, Hussain A, et al. A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 2013; 72(3): 537-44.
[104]
Ramalingam SS, Maitland ML, Frankel P, et al. Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 2010; 28(1): 56-62.
[105]
Stadler WM, Margolin K, Ferber S, McCulloch W, Thompson JA. A phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin Genitourin Cancer 2006; 5(1): 57-60.
[106]
Schrump DS, Fischette MR, Nguyen DM, et al. Clinical and molecular responses in lung cancer patients receiving Romidepsin. Clin Cancer Res 2008; 14(1): 188-98.
Related Journals
Current Drug Safety
Current Medicinal Chemistry
Current Neuropharmacology
Current Pharmaceutical Analysis
Current Topics in Medicinal Chemistry
Current Vascular Pharmacology
Current Respiratory Medicine Reviews
Infectious Disorders - Drug Targets
Endocrine, Metabolic & Immune Disorders - Drug Targets
CNS & Neurological Disorders - Drug Targets
Related Books
New Findings from Natural Substances
Mitochondrial DNA and the Immuno-inflammatory Response: New Frontiers to Control Specific Microbial Diseases
Pharmaceutical Chemistry and Production: An Introductory Textbook
Evidence-Based Research in Ayurveda against COVID-19 in Compliance with Standardized Protocols and Practices
Frontiers in Clinical Drug Research – Anti Allergy Agents
Pharmaceuticals for Targeting Coronaviruses
Medical Applications of Beta-Glucan
Nanotechnology Driven Herbal Medicine for Burns: From Concept to Application
Postbiotics: Science, Technology and Applications
Frontiers in Inflammation
Article Metrics
43
6