Promises and challenges of anticancer drugs that target the epigenome.

The occurrence of epigenetic aberrations in cancer and their role in promoting tumorigenesis has led to the development of various small molecule inhibitors that target epigenetic enzymes. In preclinical settings, many epigenetic inhibitors demonstrate promising activity against a variety of both hematological and solid tumors. The therapeutic efficacy of those inhibitors that have entered the clinic however, is restricted predominantly to hematological malignancies. Here we outline the observed epigenetic aberrations in various types of cancer and the clinical responses to epigenetic drugs. We furthermore discuss strategies to improve the responsiveness of both hematological and solid malignancies to epigenetic drugs.

[1]  A. Nudelman,et al.  The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity , 2012, Investigational New Drugs.

[2]  Chuan He,et al.  Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine , 2011, Science.

[3]  O. Abdel-Wahab,et al.  Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. , 2011, Cancer cell.

[4]  S. Armstrong,et al.  Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. , 2011, Cancer cell.

[5]  P. Opolon,et al.  TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. , 2011, Cancer cell.

[6]  J. Szer,et al.  MLL-aberrant leukemia: complete cytogenetic remission following treatment with a histone deacetylase inhibitor (HDACi) , 2011, Annals of Hematology.

[7]  Yi Zhang,et al.  DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. , 2011, Blood.

[8]  B. Skikne,et al.  Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  H. de Thé,et al.  Revisiting the differentiation paradigm in acute promyelocytic leukemia. , 2011, Blood.

[10]  S. Steinberg,et al.  Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. , 2011, Blood.

[11]  Philipp Kapranov,et al.  Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells , 2011, Nature.

[12]  B. Quesnel,et al.  Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias , 2011, Leukemia.

[13]  Juri Rappsilber,et al.  TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity , 2011, Nature.

[14]  W. Reik,et al.  Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation , 2011, Nature.

[15]  Yong-mei Zhu,et al.  Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia , 2011, Nature Genetics.

[16]  Keji Zhao,et al.  Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells , 2011, Nature.

[17]  David A. Orlando,et al.  The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma , 2011, Nature.

[18]  Li Ding,et al.  Recurrent DNMT3A Mutations in Patients with Myelodysplastic Syndromes , 2011, Leukemia.

[19]  T. Mak,et al.  Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development , 2011, PloS one.

[20]  Kenneth H. Buetow,et al.  CREBBP mutations in relapsed acute lymphoblastic leukaemia , 2011, Nature.

[21]  M. Esteller,et al.  Cancer epigenetics reaches mainstream oncology , 2011, Nature Medicine.

[22]  K. Döhner,et al.  TET genes: new players in DNA demethylation and important determinants for stemness. , 2011, Experimental hematology.

[23]  Arul M Chinnaiyan,et al.  Metabolism unhinged: IDH mutations in cancer , 2011, Nature Medicine.

[24]  P. Grandi,et al.  Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes , 2011, Nature Biotechnology.

[25]  Ryan D. Morin,et al.  Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. , 2011, Blood.

[26]  R. Johnstone,et al.  Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies , 2011, Proceedings of the National Academy of Sciences.

[27]  Riitta Lahesmaa,et al.  Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. , 2011, Cell stem cell.

[28]  A. Oza,et al.  Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas , 2011, Clinical Cancer Research.

[29]  M. D. Reed,et al.  Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. , 2011, Cancer research.

[30]  J. Maciejewski,et al.  Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher‐risk myelodysplastic syndromes , 2011, American journal of hematology.

[31]  Raul Rabadan,et al.  Inactivating mutations of acetyltransferase genes in B-cell lymphoma , 2010, Nature.

[32]  Joshua F. McMichael,et al.  DNMT3A mutations in acute myeloid leukemia. , 2010, The New England journal of medicine.

[33]  J. Licht,et al.  Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. , 2010, Cancer cell.

[34]  D. Herranz,et al.  SIRT1: recent lessons from mouse models , 2010, Nature Reviews Cancer.

[35]  Haikuo Zhang,et al.  TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine , 2010, Cell Research.

[36]  L. Aravind,et al.  Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 , 2010, Nature.

[37]  R. Copeland,et al.  Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas , 2010, Proceedings of the National Academy of Sciences.

[38]  M. Lübbert,et al.  Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy , 2010, Clinical Epigenetics.

[39]  P. Atadja,et al.  Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T‐cell lymphoma models: Defining molecular mechanisms of resistance , 2010, International journal of cancer.

[40]  J. Becker,et al.  Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  D. Neuberg,et al.  Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: A children's oncology group study , 2010, Pediatric blood & cancer.

[42]  M. Esteller,et al.  Epigenetic modifications and human disease , 2010, Nature Biotechnology.

[43]  Ali Shilatifard,et al.  Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis , 2010, Nature Reviews Cancer.

[44]  G. Garcia-Manero,et al.  Safety and efficacy of azacitidine in myelodysplastic syndromes , 2010, Drug design, development and therapy.

[45]  Yi Zhang,et al.  Active DNA demethylation: many roads lead to Rome , 2010, Nature Reviews Molecular Cell Biology.

[46]  Yi Zhang,et al.  Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification , 2010, Nature.

[47]  H. Drexler,et al.  Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders , 2010, Nature Genetics.

[48]  Y. Furukawa,et al.  Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma. , 2010, Blood.

[49]  Makoto Hasegawa,et al.  Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors. , 2010, Journal of medicinal chemistry.

[50]  C. Jung,et al.  Differential CARM1 expression in prostate and colorectal cancers , 2010, BMC Cancer.

[51]  Peter A. Jones,et al.  S110, a 5-Aza-2′-Deoxycytidine–Containing Dinucleotide, Is an Effective DNA Methylation Inhibitor In vivo and Can Reduce Tumor Growth , 2010, Molecular Cancer Therapeutics.

[52]  H. Dombret,et al.  Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome , 2010, Oncotarget.

[53]  S. Jagannath,et al.  Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: a case series illustrating utility in clinical practice. , 2010, Clinical lymphoma, myeloma & leukemia.

[54]  David J. Kerr,et al.  HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy , 2010, Proceedings of the National Academy of Sciences.

[55]  Helen M. Blau,et al.  Reprogramming towards pluripotency requires AID-dependent DNA demethylation , 2010, Nature.

[56]  S. Yalkowsky,et al.  Stability of 5-Fluoro-2′-deoxycytidine and Tetrahydrouridine in Combination , 2010, AAPS PharmSciTech.

[57]  A. Rambaldi,et al.  A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma , 2010, Annals of Hematology.

[58]  A. Lakshmikuttyamma,et al.  Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition , 2010, Oncogene.

[59]  Ryan D. Morin,et al.  Somatic mutation of EZH2 (Y641) in Follicular and Diffuse Large B-cell Lymphomas of Germinal Center Origin , 2010, Nature Genetics.

[60]  David C. Smith,et al.  Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862) , 2009, Cancer.

[61]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[62]  Gurpreet W. Tang,et al.  Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes , 2009, Nature.

[63]  A. Lane,et al.  Histone deacetylase inhibitors in cancer therapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  S. Steinberg,et al.  Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  J. Herman,et al.  A Phase I Dose-Finding Study of 5-Azacytidine in Combination with Sodium Phenylbutyrate in Patients with Refractory Solid Tumors , 2009, Clinical Cancer Research.

[66]  Keith D Robertson,et al.  A Novel DNMT3B Splice Variant Expressed in Tumor and Pluripotent Cells Modulates Genomic DNA Methylation Patterns and Displays Altered DNA Binding , 2009, Molecular Cancer Research.

[67]  Jeffrey W. Scott,et al.  Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma , 2009, British journal of haematology.

[68]  M. Toyota,et al.  Elevated Dnmt3a activity promotes polyposis in Apc(Min) mice by relaxing extracellular restraints on Wnt signaling. , 2009, Gastroenterology.

[69]  Robert A. Copeland,et al.  Protein methyltransferases as a target class for drug discovery , 2009, Nature Reviews Drug Discovery.

[70]  S. Grant,et al.  Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma , 2009, Clinical Cancer Research.

[71]  M. Mann,et al.  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions , 2009, Science.

[72]  T. Heinzel,et al.  HDACi--targets beyond chromatin. , 2009, Cancer letters.

[73]  E. Galanis,et al.  Vorinostat in solid and hematologic malignancies , 2009, Journal of hematology & oncology.

[74]  A. Hagemeijer,et al.  Acquired mutations in TET2 are common in myelodysplastic syndromes , 2009, Nature Genetics.

[75]  R. Slany.  The molecular biology of mixed lineage leukemia , 2009, Haematologica.

[76]  J. Issa,et al.  Targeting DNA Methylation , 2009, Clinical Cancer Research.

[77]  R. Johnstone,et al.  Rational Combinations Using HDAC Inhibitors , 2009, Clinical Cancer Research.

[78]  Yue-hua Ma,et al.  New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer , 2009, Journal of hematology & oncology.

[79]  Shuji Ogino,et al.  DNMT3B Expression Might Contribute to CpG Island Methylator Phenotype in Colorectal Cancer , 2009, Clinical Cancer Research.

[80]  I. Wistuba,et al.  Decitabine Effect on Tumor Global DNA Methylation and Other Parameters in a Phase I Trial in Refractory Solid Tumors and Lymphomas , 2009, Clinical Cancer Research.

[81]  Ricky W. Johnstone,et al.  Epigenetics in cancer: Targeting chromatin modifications , 2009, Molecular Cancer Therapeutics.

[82]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1 , 2009, Science.

[83]  Robert Brown,et al.  The promises and pitfalls of epigenetic therapies in solid tumours. , 2009, European journal of cancer.

[84]  Laura Vidal,et al.  Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors , 2009, Clinical Cancer Research.

[85]  Caterina Giannini,et al.  Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  J. Downing,et al.  Mouse models of human AML accurately predict chemotherapy response. , 2009, Genes & development.

[87]  A. Shilatifard,et al.  An operational definition of epigenetics. , 2009, Genes & development.

[88]  Paul A. Northcott,et al.  Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma , 2009, Nature Genetics.

[89]  G. Wilding,et al.  Vorinostat (NSC# 701852) in Patients with Relapsed Non-small Cell Lung Cancer: A Wisconsin Oncology Network Phase II Study , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[90]  Bin Tean Teh,et al.  Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer , 2009, Nature Genetics.

[91]  Valeria Santini,et al.  Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. , 2009, The Lancet. Oncology.

[92]  R. Johnstone,et al.  Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. , 2009, Blood.

[93]  D. Banerjee,et al.  Molecular targets for epigenetic therapy of cancer. , 2009, Current pharmaceutical biotechnology.

[94]  R. Bernards,et al.  Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. , 2009, Cancer cell.

[95]  D. Gandara,et al.  Phase II Study of Belinostat (PXD101), a Histone Deacetylase Inhibitor, for Second Line Therapy of Advanced Malignant Pleural Mesothelioma , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[96]  E. Giovannucci,et al.  A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. , 2008, Journal of the National Cancer Institute.

[97]  G. Weiss,et al.  MicroRNAs and cancer: past, present, and potential future , 2008, Molecular Cancer Therapeutics.

[98]  A. Krasnitz,et al.  An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer , 2008, Cell.

[99]  R. Larson,et al.  Histone Deacetylase Inhibitor Romidepsin Has Differential Activity in Core Binding Factor Acute Myeloid Leukemia , 2008, Clinical Cancer Research.

[100]  L. Thompson,et al.  Therapeutic application of histone deacetylase inhibitors for central nervous system disorders , 2008, Nature Reviews Drug Discovery.

[101]  B. Keppler,et al.  Chromatin-modifying enzymes as therapeutic targets – Part 1 , 2008, Expert opinion on therapeutic targets.

[102]  I. Christensen,et al.  A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia , 2008, European journal of haematology.

[103]  M. Minden,et al.  Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. , 2008, Blood.

[104]  Jessica E. Bolden,et al.  Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist , 2008, Proceedings of the National Academy of Sciences.

[105]  A. Hauschild,et al.  Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma , 2008, Melanoma research.

[106]  M. Rothenberg,et al.  A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor, MS-275, in Patients with Refractory Solid Tumors and Lymphomas , 2008, Clinical Cancer Research.

[107]  Gordon K Smyth,et al.  Histone Deacetylase Inhibitor Panobinostat Induces Clinical Responses with Associated Alterations in Gene Expression Profiles in Cutaneous T-Cell Lymphoma , 2008, Clinical Cancer Research.

[108]  James H. Doroshow,et al.  Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU) , 2008, Cancer Chemotherapy and Pharmacology.

[109]  D. Gold,et al.  Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation , 2008, Nature Genetics.

[110]  C. Paweletz,et al.  Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. , 2008, Cancer research.

[111]  K. Helin,et al.  Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. , 2008, Genes & development.

[112]  W. Hahn,et al.  The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth , 2008, PloS one.

[113]  J. Byrd,et al.  A Phase I Biological Study of MG98, an Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-Risk Myelodysplasia and Acute Myeloid Leukemia , 2008, Clinical Cancer Research.

[114]  R. Yeh,et al.  Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells , 2008, Oncogene.

[115]  M. Esteller.  Epigenetics in cancer. , 2008, The New England journal of medicine.

[116]  E. Seto,et al.  The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men , 2008, Nature Reviews Molecular Cell Biology.

[117]  P. Pandolfi,et al.  Tolerability, Pharmacodynamics, and Pharmacokinetics Studies of Depsipeptide (Romidepsin) in Patients with Acute Myelogenous Leukemia or Advanced Myelodysplastic Syndromes , 2008, Clinical Cancer Research.

[118]  Yukihiro Itoh,et al.  Isoform-selective histone deacetylase inhibitors. , 2008, Current pharmaceutical design.

[119]  Robert Brown,et al.  A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors , 2008, Clinical Cancer Research.

[120]  W. Sippl,et al.  Inhibitors of NAD+ dependent histone deacetylases (sirtuins). , 2008, Current pharmaceutical design.

[121]  R. Jaenisch,et al.  Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. , 2007, Genes & development.

[122]  H. Nakshatri,et al.  MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB–dependent promoters , 2007 .

[123]  F. Lo‐Coco,et al.  Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. , 2007, Cancer cell.

[124]  Andreas Schätzlein,et al.  Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[125]  Jorge Cortes,et al.  Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. , 2007, Blood.

[126]  J. Doroshow,et al.  Phase I Trial of MS-275, a Histone Deacetylase Inhibitor, Administered Weekly in Refractory Solid Tumors and Lymphoid Malignancies , 2007, Clinical Cancer Research.

[127]  J. Griffith,et al.  5-Azacytidine induced methyltransferase-DNA adducts block DNA replication in vivo. , 2007, Cancer research.

[128]  M. Grever,et al.  Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[129]  John Lough,et al.  Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response , 2007, Nature.

[130]  M. L. Beau,et al.  Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins , 2007, Oncogene.

[131]  T. Kuzel,et al.  Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[132]  S. Steinberg,et al.  Clinical and Molecular Responses in Lung Cancer Patients Receiving Romidepsin , 2007, Clinical Cancer Research.

[133]  M. Grunstein,et al.  Functions of site-specific histone acetylation and deacetylation. , 2007, Annual review of biochemistry.

[134]  S. Ramalingam,et al.  Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies , 2007, Clinical Cancer Research.

[135]  M. Fishman,et al.  Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[136]  Mark J. Smyth,et al.  Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma , 2007, Proceedings of the National Academy of Sciences.

[137]  K. He,et al.  Vorinostat for Treatment of Cutaneous Manifestations of Advanced Primary Cutaneous T-Cell Lymphoma , 2007, Clinical Cancer Research.

[138]  E. Sausville,et al.  Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. , 2007, Blood.

[139]  Jerry L. Workman,et al.  Histone acetyltransferase complexes: one size doesn't fit all , 2007, Nature Reviews Molecular Cell Biology.

[140]  T. Habuchi,et al.  Low concentrations of the histone deacetylase inhibitor, depsipeptide, enhance the effects of gemcitabine and docetaxel in hormone refractory prostate cancer cells. , 2007, Oncology reports.

[141]  K. Bible,et al.  Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress. , 2007, Blood.

[142]  E. Lander,et al.  The Mammalian Epigenome , 2007, Cell.

[143]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[144]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[145]  H. Kantarjian,et al.  Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia , 2007, Cancer.

[146]  C. Pérez-Plasencia,et al.  A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors , 2007, BMC Cancer.

[147]  Michael Rytting,et al.  Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. , 2006, Blood.

[148]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[149]  S. Vandenberg,et al.  Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. , 2006, Cancer research.

[150]  Yi Zhang,et al.  JmjC-domain-containing proteins and histone demethylation , 2006, Nature Reviews Genetics.

[151]  R. Larson,et al.  Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[152]  L. Mahadevan,et al.  Enhanced histone acetylation and transcription: a dynamic perspective. , 2006, Molecular cell.

[153]  K. Bhalla,et al.  A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies , 2006, Clinical Cancer Research.

[154]  S. Jang,et al.  A novel DNMT3B subfamily, DeltaDNMT3B, is the predominant form of DNMT3B in non-small cell lung cancer. , 2006, International journal of oncology.

[155]  L. Aaltonen,et al.  A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition , 2006, Nature Genetics.

[156]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[157]  John M Bennett,et al.  Decitabine improves patient outcomes in myelodysplastic syndromes , 2006, Cancer.

[158]  R. DePinho,et al.  Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. , 2006, Cancer research.

[159]  Karl P Nightingale,et al.  Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. , 2006, Current opinion in genetics & development.

[160]  E. Eisenhauer,et al.  Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: A National Cancer Institute of Canada Clinical Trials Group investigational new drug study , 2006, Investigational New Drugs.

[161]  M. Fraga,et al.  The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma. , 2006, Blood.

[162]  E. Seto,et al.  Acetylation and deacetylation of non-histone proteins. , 2005, Gene.

[163]  G. Fuhrmann,et al.  The ability of E1A to rescue ras-induced premature senescence and confer transformation relies on inactivation of both p300/CBP and Rb family proteins. , 2005, Cancer research.

[164]  T. Bestor,et al.  Eukaryotic cytosine methyltransferases. , 2005, Annual review of biochemistry.

[165]  E. Sausville,et al.  Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[166]  K. Ghoshal,et al.  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 , 2005, Molecular and Cellular Biology.

[167]  Alexander V. Lyubimov,et al.  Plasma Pharmacokinetics, Oral Bioavailability, and Interspecies Scaling of the DNA Methyltransferase Inhibitor, Zebularine , 2005, Clinical Cancer Research.

[168]  D. Reinberg,et al.  The key to development: interpreting the histone code? , 2005, Current opinion in genetics & development.

[169]  M. Fraga,et al.  Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer , 2005, Nature Genetics.

[170]  M. Grever,et al.  A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. , 2004, Blood.

[171]  J. Hess.  MLL: a histone methyltransferase disrupted in leukemia. , 2004, Trends in molecular medicine.

[172]  H. Keer,et al.  Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. , 2004, Lung cancer.

[173]  Xiang-Jiao Yang.  The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. , 2004, Nucleic acids research.

[174]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[175]  S. Hirohashi,et al.  Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder. , 2003, The Journal of urology.

[176]  Debashis Ghosh,et al.  EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[177]  L. Schwartz,et al.  Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[178]  A. Bird,et al.  Deficiency of Mbd2 suppresses intestinal tumorigenesis , 2003, Nature Genetics.

[179]  S. Hirohashi,et al.  Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. , 2003, Cancer letters.

[180]  J. Marshall,et al.  A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. , 2002, Journal of experimental therapeutics & oncology.

[181]  Wei Gu,et al.  Acetylation inactivates the transcriptional repressor BCL6 , 2002, Nature Genetics.

[182]  A. Feinberg,et al.  DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms. , 2002, Seminars in cancer biology.

[183]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[184]  Bert Vogelstein,et al.  DNMT1 and DNMT3b cooperate to silence genes in human cancer cells , 2002, Nature.

[185]  P. Laird,et al.  Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. , 2002, Cancer research.

[186]  S. Bates,et al.  Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[187]  P. Pandolfi,et al.  Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. , 2001, The Journal of clinical investigation.

[188]  R. Weinberg,et al.  hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase , 2001, Cell.

[189]  D. Reinberg,et al.  Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. , 2001, Genes & development.

[190]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[191]  B. Johansson,et al.  Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). , 2001, Human molecular genetics.

[192]  U. Kees,et al.  Promoter demethylation accompanies reactivation of the HOX11 proto‐oncogene in leukemia , 2000, Genes, chromosomes & cancer.

[193]  A. Bird,et al.  Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[194]  Carlos Caldas,et al.  Mutations truncating the EP300 acetylase in human cancers , 2000, Nature Genetics.

[195]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[196]  Peter A. Jones,et al.  Cancer-epigenetics comes of age , 1999, Nature Genetics.

[197]  E Gabrielson,et al.  Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[198]  R. Jaenisch,et al.  Baculovirus-mediated expression and characterization of the full-length murine DNA methyltransferase. , 1997, Nucleic acids research.

[199]  M. Grunstein.  Histone acetylation in chromatin structure and transcription , 1997, Nature.

[200]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[201]  M. Eccles,et al.  Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour , 1993, Nature.

[202]  C. Zwaan,et al.  TET2 mutations in childhood leukemia , 2011, Leukemia.

[203]  Z. Herceg,et al.  Histone modifications and cancer. , 2010, Advances in genetics.

[204]  W. Sippl,et al.  Cancer treatment of the future: inhibitors of histone methyltransferases. , 2009, The international journal of biochemistry & cell biology.

[205]  M. Esteller,et al.  DNA methylomes, histone codes and miRNAs: tying it all together. , 2009, The international journal of biochemistry & cell biology.

[206]  P. Molloy,et al.  DNA hypomethylation and human diseases. , 2007, Biochimica et biophysica acta.

[207]  M. Esteller,et al.  DNA methylation and histone modifications in patients with cancer: potential prognostic and therapeutic targets. , 2007, Methods in molecular biology.

[208]  Chunlei Zhang,et al.  Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). , 2007, Blood.

[209]  A. Feinberg,et al.  The epigenetic progenitor origin of human cancer , 2006, Nature Reviews Genetics.

[210]  A. Zelenetz,et al.  Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[211]  From bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 23, 2013. For personal use , 2006 .

[212]  M. Robert,et al.  DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells , 2003, Nature Genetics.

[213]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[214]  A. Feinberg,et al.  Alterations in DNA methylation in human colon neoplasia. , 1987, Seminars in surgical oncology.

[215]  Jacqueline S. Garcia,et al.  Oncotargets and Therapy Dovepress Open Access to Scientific and Medical Research Open Access Full Text Article Dovepress an Update on the Safety and Efficacy of Decitabine in the Treatment of Myelodysplastic Syndromes , 2022 .