Histone acetylation: novel target for the treatment of acute lymphoblastic leukemia

Clinical Epigenetics

Xi Zhang¹  Michael F. Press²  Xue-Lian Chen³  Andres Stucky³  Jiang F. Zhong³  Cheng Zhang¹ 

[1] Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People’s Republic of China;Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles 90033, CA, USA;Department of Pediatric, Keck School of Medicine, University of Southern California, Los Angeles 90033, CA, USA

关键词: Clinical application;    Biomarker;    Histone deacetylase;    Histone acetyltransferase;    Acute lymphoblastic leukemia;    Histone acetylation;   

Others  :  1234371
DOI  :  10.1186/s13148-015-0151-8

 received in 2015-09-16, accepted in 2015-10-27,  发布年份 2015

【 摘 要 】

Acute lymphoblastic leukemia (ALL) has been generally considered a genetic disease (disorder) with an aggressive tumor entity of highly proliferative malignant lymphoid cells. However, in recent years, significant advances have been made in the elucidation of the ALL-associated processes. Thus, we understand that histone acetylation is involved in the permanent changes of gene expression controlling ALL developmental outcomes. In this article, we will focus on histone acetylation associated with ALL, their implications as biomarkers for prognostic, and their preclinical and clinical applications.

【 授权许可】

   
2015 Zhang et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Bhojwani D, Pui CH: Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013, 14:e205-17.
• [2]Ting AH, McGarvey KM, Baylin SB: The cancer epigenome-components and functional correlates. Genes Dev. 2006, 20:3215-31.
• [3]Baylin SB, Jones PA: A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer. 2011, 11:726-34.
• [4]Marmorstein R: Structure of histone acetyltransferases. J Mol Biol. 2001, 311:433-44.
• [5]Talbert PB, Henikoff S: Histone variants-ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol. 2010, 11:264-75.
• [6]Zhou VW, Goren A, Bernstein BE: Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011, 12:7-18.
• [7]Kevin S: Histone acetylation and transcriptional regulatory mechnisms. Genes Dev. 1998, 12:599-606.
• [8]Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al.: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009, 325:834-40.
• [9]Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M: The growing landscape of lysine acetylation links metabolism and cell signaling. Nat Rev Mol Cell Biol. 2014, 15:536-50.
• [10]Haberland M, Montgomery RL, Olson EN: The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009, 10:32-42.
• [11]Peng L, Seto E: Deacetylation of nonhistone proteins by HDACs and the implications in cancer. Handb Exp Pharmacol. 2011, 206:39-56.
• [12]Jenuwein T, Allis CD: Translating the histone code. Science. 2001, 293:1074-80.
• [13]Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, et al.: Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008, 40:897-903.
• [14]Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, et al.: Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000, 406:593-9.
• [15]Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J: A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011, 470:279-83.
• [16]Vidali G, Gershey EL, Allfrey VG: Chemical studies of histone acetylation. The distribution of ϵ-N-acetyllysine in calf thymus histones. J Biol Chem 1968, 243:6361-6.
• [17]Zentner GE, Henikoff S: Regulation of nucleosome dynamics by histone modifications. Nat Struct mol Biol. 2013, 20:259-66.
• [18]Spange S, Wagner T, Heinzel T, Krämer OH: Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2009, 41:185-98.
• [19]Cheung P, Allis CD, Sassone-Corsi P: Signaling to chromatin through histone modifications. Cell. 2000, 103:263-71.
• [20]Winston F, Allis CD: The bromodomain: a chromatin-targeting module? Nat Struct Biol. 1999, 6:601-4.
• [21]Chi P, Allis CD, Wang GG: Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 2010, 10:457-69.
• [22]Barratt MJ, Hazzalin CA, Cano E, Mahadevan LC: Mitogen-stimulated phosphorylation of histone H3 is targeted to a small hyperacetylation-sensitive fraction. P Natl Acad Sci USA 1994, 91:4781-5.
• [23]Panagis F, Stefan K: Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014, 13:337-56.
• [24]Kraszewska MD, Dawidowska M, Larmonie NS, Kosmalska M, Sedek L, Szczepaniak M, et al.: DNA methylation pattern is altered in childhood T cell acute lymphoblastic leukemia patients as compared with normal thymic subsets: insights into CpG island methylator phenotype in T-ALL. Leukemia. 2012, 26:367-71.
• [25]Di Croce L: Chromatin modifying activity of leukaemia associated fusion proteins. Hum Mol Genet. 2005, 14:R77-84.
• [26]Pigazzi M, Manara E, Baron E, Basso G: ICER expression inhibits leukemia phenotype and controls tumor progression. Leukemia. 2008, 22:2217-25.
• [27]Pui CH, Mullighan CG, Evans WE, Relling MV: Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012, 120:1165-74.
• [28]Inthal A, Zeitlhofer P, Zeginigg M, Morak M, Grausenburger R, Fronkova E, et al.: CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia. Leukemia. 2012, 26:1797-803.
• [29]Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, et al.: CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011, 471:235-39.
• [30]Kung AL, Rebel VI, Bronson RT, Ch'ng LE, Sieff CA, Livingston DM, et al.: Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 2000, 14:272-7.
• [31]Shigeno K, Yoshida H, Pan L, Luo JM, Fujisawa S, Naito K, et al.: Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias. Cancer Lett. 2004, 213:11-20.
• [32]Holmlund T, Lindberg MJ, Grander D, Wallberg AE: GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia. Leukemia. 2012, 27:578-85.
• [33]Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, et al.: The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012, 481:157-63.
• [34]Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, et al.: Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 2012, 18:298-301.
• [35]Caravatta L, Sancilio S, di Giacomo V, Rana R, Cataldi A, Di Pietro R: PI3-K/Akt-dependent activation of cAMP-response element-binding (CREB) protein in Jurkat T leukemia cells treated with TRAIL. J Cell Physiol. 2008, 214:192-200.
• [36]Moreno DA, Scrideli CA, Cortez MA, de Paula QR, Valera ET, da Silva SV, et al.: Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol. 2010, 150:665-73.
• [37]Tao YF, Pang L, Du XJ, Sun LC, Hu SY, Lu J, et al.: Differential mRNA expression levels of human histone-modifying enzymes in normal karyotype B cell pediatric acute lymphoblastic leukemia. Int J Mol Sci. 2013, 14:3376-94.
• [38]Sonnemann J, Gruhn B, Wittig S, Becker S, Beck JF: Increased activity of histone deacetylases in childhood acute lymphoblastic leukaemia and acute myeloid leukaemia: support for histone deacetylase inhibitors as antileukaemic agents. Br J Haematol. 2012, 158:664-6.
• [39]Advani AS, Gibson SE, Douglas E, Jin T, Zhao X, Kalaycio M, et al.: Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients. BMC Cancer. 2010, 10:387. BioMed Central Full Text
• [40]Advani AS, Gibson S, Douglas E, Diacovo J, Elson P, Kalaycio M, et al.: Histone H4 acetylation by immunohistochemistry and prognosis in relapsed acute lymphocytic leukaemia (ALL). Br J Haematol. 2011, 153:504-7.
• [41]Gruhn B, Naumann T, Gruner D, Walther M, Wittig S, Becker S, et al.: The expression of histone deacetylase 4 is associated with prednisone poor-response in childhood acute lymphoblastic leukemia. Leuk Res. 2013, 37:1200-7.
• [42]Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, et al.: Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 2005, 19:1751-9.
• [43]Vernarecci S, Tosi F, Filetici P: Tuning acetylated chromatin with HAT inhibitors: a novel tool for therapy. Epigenetics. 2010, 5:105-11.
• [44]Fulda S: Modulation of TRAIL-induced apoptosis by HDAC inhibitors. Curr Cancer Drug Targets. 2008, 8:132-40.
• [45]Hrebackova J, Hrabeta J, Eckschlager T: Valproic acid in the complex therapy of malignant tumors. Curr Drug Targets. 2010, 11:361-79.
• [46]Chiao MT, Cheng WY, Yang YC, Shen CC, Ko JL: Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells. Autophagy. 2013, 9:1509-26.
• [47]Juengel E, Nowaz S, Makarevi J, Natsheh I, Werner I, Nelson K, et al.: HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A. Mol Cancer. 2014, 13:152. BioMed Central Full Text
• [48]Chodurek E, Kulczycka A, Orchel A, Aleksander-Konert E, Dzierzewicz Z: Effect of valproic acid on the proliferation and apoptosis of the human melanoma G-361 cell line. Acta Pol Pharm. 2014, 71:917-21.
• [49]Banerji U, van Doorn L, Papadatos-Pastos D, Kristeleit R, Debnam P, Tall M, et al.: A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors. Clin Cancer Res. 2012, 18:2687-94.
• [50]Dong M, Ning ZQ, Xing PY, Xu JL, Cao HX, Dou GF, et al.: Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas. Cancer Chemother Pharmacol. 2012, 69:1413-22.
• [51]Chen HP, Zhao YT, Zhao TC: Histone deacetylases and mechanisms of regulation of gene expression. Crit Rev Oncog. 2015, 20:35-47.
• [52]Jones PA, Baylin SB: The epigenomics of cancer. Cell. 2007, 128:683-92.
• [53]Dokmanovic M, Clarke C, Marks PA: Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007, 5:981-9.
• [54]Islam AB, Richter WF, Jacobs LA, Lopez-Bigas N, Benevolenskaya EV: Co-regulation of histone-modifying enzymes in cancer. PLoS One. 2011, 6:e24023.
• [55]Kim HJ, Bae SC: Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 2011, 3:166-79.
• [56]Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al.: Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007, 109:31-9.
• [57]Campas-Moya C: Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today (Barc) 2009, 45:787-95.
• [58]Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H, et al.: FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer. 2002, 62:4916-21.
• [59]Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007, 26:5541-52.
• [60]Dell'Aversana C, Lepore I, Altucci L: HDAC modulation and cell death in the clinic. Exp Cell Res. 2012, 318:1229-44.
• [61]Richon VM, Garcia-Vargas J, Hardwick JS: Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett. 2009, 280:201-10.
• [62]Butler LM, Agus DB, Agus DB: Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 2000, 60:5165-70.
• [63]Duvic M, Vu J: Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Investig Drugs 2007, 16:1111-1120.
• [64]Batty N, Malouf GG, Issa JPJ: Histone deacetylase inhibitors as anti-neoplastic agents. Cancer Lett. 2009, 280:192-200.
• [65]Vrana JA, Decker RH, Decker RH: Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-x(L), c-Jun, and p21(CIP1), but independent of p53. Oncogene. 1999, 18:7016-25.
• [66]Einsiedel HG, Kawan L, Eckert C, Witt O, Fichtner I, Henze G, et al.: Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia. Leukemia. 2006, 20:1435-6.
• [67]Leclerc GJ, Mou C, Leclerc GM, Mian AM, Barredo JC: Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia. 2010, 24:552-62.
• [68]Bachmann PS, Piazza RG, Janes ME, Wong NC, Davies C, Mogavero A, et al.: Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition. Blood. 2010, 116:3013-22.
• [69]Burke MJ. Decitabine, vorinostat, and combination chemotherapy in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma that has relapsed or not responded to treatment. http://clinicaltrials.gov/ct2/show/NCT00882206. Access date: Dec 1, 2014.
• [70]Burke MJ. A pilot study of decitabine and vorinostat with chemotherapy for relapsed ALL. https://clinicaltrials.gov/ct2/show/NCT01483690. Access date: Dec 1, 2014.
• [71]Vilas-Zornoza A, Agirre X, Abizanda G, Moreno C, Segura V, De Martino RA, et al.: Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia. Leukemia. 2012, 26:1517-26.
• [72]Kircher B, Shcumacher P, Petzer A, Hoflehner E, Haun M, Wolf AM, et al.: Anti-leukemic activity of valproic acid and imatinib mesylate on human Ph + ALL and CML cells in vitro. Eur J Haematol. 2009, 83:48-56.
• [73]Tsapis M, Lieb M, Manzo F, Shankaranarayanan P, Herbrecht R, Lutz P, et al.: HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway. Int. J. Biochem. Cell Biol. 2007, 39:1500-9.
• [74]Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P, et al.: The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph-acute lymphoblastic leukemia cells. Blood. 2008, 111:5093-100.
• [75]Bastian L, Hof J, Pfau M, Fichtner I, Eckert C, Henze G, et al.: Synergistic activity of bortezomib and HDACi in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT, and NF-kappaB. Clin Cancer Res. 2013, 19:1445-57.
• [76]Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, et al.: HDAC inhibitors potentiate the activity of the BCR/ ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo. Clin Cancer. 2011, 17:3219-32.
• [77]Okabe S, Tauchi T, Ohyashiki K: Efficacy of MK-0457 and in combination with vorinostat against Philadelphia chromosome positive acute lymphoblastic leukemia cells. Ann Hematol. 2010, 89:1081-7.
• [78]Keshelava N, Houghton PJ, Morton CL, Lock RB, Carol H, Keir ST, et al.: Initial testing (stage 1) of vorinostat (SAHA) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009, 53:505-8.
• [79]Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, et al.: A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res. 2006, 12:4628-35.
• [80]Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al.: Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 2008, 111:1060-6.
• [81]Lee-Sherick AB, Linger RM, Gore L, Keating AK, Graham DK: Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development. Br J Haematol. 2010, 151:295-311.
• [82]Lee L, Fielding AK: Emerging pharmacotherapies for adult patients with acute lymphoblastic leukemia. Clin Med Insights Oncol. 2012, 6:85-100.
• [83]Romanski A, Bacic B, Bug G, Pfeifer H, Gul H, Remiszewski S, et al.: Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia. Haematologica. 2004, 89:419-26.
• [84]Gore SD, Weng LJ, Zhai S, Figg WD, Donehower RC, Dover GJ, et al.: Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2001, 7:2330-9.
• [85]Batova A, Shao LE, Diccianni MB, Yu AL, Tanaka T, Rephaeli A, et al.: The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines. Blood. 2002, 100:3319-24.
• [86]Chateauvieux S, Morceau F, Dicato M, Diederich M: Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010, 2010:479364.
• [87]Miao M, Du B, Hu R, Yang Y, Yang W, Liao AJ, et al.: Effect of valproic acid sodium on proliferation and apoptosis of acute T-lymphoblastic leukemia Jurkat cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013, 21:343-6.
• [88]Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, Hoshino K, Quintas-Cardama A, Richon VM, et al.: Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor. Blood. 2006, 108:1174-82.
• [89]Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G: Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk Res. 2005, 29:739-48.
• [90]Masetti R, Serravalle S, Biagi C, Pession A: The role of HDACs inhibitors in childhood and adolescence acute leukemias. J Biomed Biotechnol. 2011, 2011:148046.
• [91]Soriano AO, Yang H, Yang H: Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007, 110:2302-8.
• [92]Chateauvieux S, Eifes S, Morceau F, Grigorakaki C, Schnekenburger M, Henry E, et al.: Valproic acid perturbs hematopoietic homeostasis by inhibition of erythroid differentiation and activation of the myelo-monocytic pathway. Biochem Pharmacol. 2011, 81:498-509.
• [93]Minucci S, Pelicci PG: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev Cancer. 2006, 6:38-51.
• [94]Rosato RR, Almenara JA, Grant S: The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res. 2003, 63:3637-45.
• [95]Gao S, Mobley A, Miller C, Boklan J, Chandra J: Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells. Leuk Res. 2008, 32:771-80.
• [96]Maggio SC, Rosato RR, Rosato RR: The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res. 2004, 64:2590-600.
• [97]Falkenberg KJ, Johnstone RW: Histone deacetylases and their inhibitors in cancer, neurological disease and immune disorders. Nat Rev Drug Discov. 2014, 13:673-91.
• [98]Peirs S, Van der Meulen J, Van de Walle I, Taghon T, Speleman F, Poppe B, et al.: Epigenetics in T-cell acute lymphoblastic leukemia. Immunol Rev. 2015, 263:50-67.
• [99]Campbell RM, Tummino PJ: Cancer epigenetics drug discovery and development: the challenge of hitting the mark. J Clin Invest. 2014, 124:64-9.
• [100]Rose NR, Klose RJ: Understanding the relationship between DNA methylation and histone lysine methylation. BBA-Gene Regul Mech. 1839, 2014:1362-72.
• [101]Cedar H, Bergman Y: Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genetics. 2009, 10:295-304.
• [102]Hatzimichael E, Crook T: Cancer epigenetics: new therapies and new challenges. J Drug Deliv. 2013, 2013:529312.