DOCSLIB.ORG

Histone Deacetylase Inhibitors Reverse Cpg Methylation by Regulating DNMT1 Through ERK Signaling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Histone Deacetylase Inhibitors Reverse Cpg Methylation by Regulating DNMT1 Through ERK Signaling ANTICANCER RESEARCH 31: 2723-2732 (2011) Histone Deacetylase Inhibitors Reverse CpG Methylation by Regulating DNMT1 through ERK Signaling SIBAJI SARKAR, ANA L. ABUJAMRA, JENNY E. LOEW, LORA W. FORMAN, SUSAN P. PERRINE and DOUGLAS V. FALLER Cancer Center, Boston University School of Medicine, Boston, MA, 02118, U.S.A. Abstract. Methylation of CpG repeats in the upstream/ (cytosine-5-)-methyltransferase 1 (DNMT1) levels. Direct promoter regions of genes is an established mechanism of inhibition of ERK activity similarly decreased DNMT1 protein gene silencing in many cell types. DNA methylation results in levels and reversed the basal hypermethylation of the the recruitment of histone deacetylases (HDACs) to promoter promoters and silencing of the RARB2, p21 and p16 tumor regions, thereby repressing expression of genes. General suppressor genes. Suppression of DNMT1 level by siRNA also inhibitors of class I and II HDACs (HDACi), such as sodium reversed methylation of these tumor suppressor genes with butyrate and suberoylanilide hydroxamic acid, suppress the similar kinetics. Collectively, these data demonstrate that growth of prostate cancer cells in vitro and in vivo. In this HDACi, by inhibiting ERK activity, regulate DNMT1 and study, we investigated the mechanism of re-expression of ultimately DNA methylation. These results demonstrate that silenced cell cycle inhibitors and retinoic acid receptor B2 HDACs regulate gene methylation, in addition to the (RARB2). HDACi inhibited cell cycle progression, and established and reciprocal ability of CpG methylation to reversed promoter methylation and silencing of three tumor recruit HDACs to repress transcription. suppressor genes: RARB2 and the cell cycle regulating cyclin- dependent kinase inhibitors p16 and p21. HDACi repressed Methylation of CpG repeats in the upstream/promoter MAP kinase I (ERK) activation and down-regulated DNA regions of genes is an established mechanism of gene silencing and is correlated with the suppression of critical genes, including tumor suppressors, in many types of tumors. The methyl-CpG-binding protein 2 (MeCP2) facilitates This article is freely accessible online. histone deacetylation and DNA methylation-dependent transcriptional silencing. For example, MeCP2 plays an Abbreviations: CpG: Cytosine phosphate guanosine; AZA: 5-aza-2’- important role in neurite extension of PC12 cells by deoxycytidine; HDAC: histone deacetylase; HDACi: histone regulating the expression of key genes involved in deacatylase inhibitors; SB: sodium butyrate; SAHA: suberoylanilide hydroxamic acid; RARB2: retinoic acid receptor beta 2; MAPK1, differentiation (1). Memory formation and synaptic plasticity mitogen-activated protein kinase 1; ERK1: MAP kinase I; AKT1: v- are regulated by DNA methylation and histone acetylation akt murine thymoma viral oncogene homolog 1; DNMTs: DNA (2). Gene silencing by methylation is also prevalent in stem (cytosine-5-)- methyl transferases; DNMT1: DNA (cytosine-5-)- cells, which undergo differentiation while proliferating (3). methyltransferase 1; CDK1: cyclin-dependent kinase 1; MEK1: DNA methylation results in the local recruitment of histone MAP2K1, mitogen-activated protein kinase kinase 1; MEK2: deacetylases (HDACs) to promoter regions with co-localization MAP2K2, mitogen-activated protein kinase kinase 2; p21: CDKN1A, of MeCP2 proteins, eventually inhibiting the binding of RNA cyclin-dependent kinase inhibitor 1A (p21, Cip1); p16: CDKN2A, cyclin-dependent kinase inhibitor 2A; siRNA: small interfering RNA; polymerase II (Pol II) and thereby repressing the expression of MS-PCR: methylation-specific polymerase chain reaction; RT-PCR: genes and their products. Such observations led to the reverse transcriptase-polymerase chain reaction; SDS-PAGE: sodium paradigm that DNA methylation lies ‘upstream’ of histone dodecyl sulphate polyacrylamide gel electrophoresis. acetylation in this pathway of transcriptional repression. While it is known that DNA methyl transferases (DNMTs) Correspondence to: Douglas V. Faller, MD, Ph.D., Cancer Center, produce methylation of CpG repeats in the upstream Boston University School of Medicine, 72 East Concord Street, K- promoter regions of genes, physiological upstream regulators 701, Boston, MA 02118, U.S.A. Tel: +1 6176384173, Fax: +1 6176384176, e-mail: [email protected] of the activity and levels of DNMTs have not been identified. Recent studies suggest that DNA methylation in colon cancer Key Words: Tumor suppressors, cell cycle arrest, DNA N-methyl cells and in NIH 3T3 cells may be regulated in some transferase, ERK. circumstances by ERK (MAP kinase1) activity (4). DNA 0250-7005/2011 $2.00+.40 2723 ANTICANCER RESEARCH 31: 2723-2732 (2011) methylation, and the enzymes which cause methylation, Cell culture. LNCaP cells were obtained directly from ATCC might be modulated directly or indirectly by the extracellular (Manassas, VA, USA), which validates cell line characterizations (ISO milieu through signal transduction pathways, which may Guide 34 accredited), and passaged in the laboratory for fewer than 3 months after receipt. LNCaP prostate cancer cells were grown in include ERK or other cellular kinases. RPMI-1640 media containing 100 IU/ml penicillin, 100 μg/ml General inhibitors of class I and II HDACs, alone or in streptomycin and 50 ml fetal bovine serum. combination with the methylation inhibitor 5-azacitydine, or its congener 5-aza-deoxycytidine (AZA), or other agents are being Cell survival assays. Viable cell enumeration was performed using studied in clinical trials for treatment of diverse types of tumors a trypan blue exclusion assay. The percentage viable cell counts (5). General (class non-specific) HDAC inhibitors (HDACi), were plotted against time of incubation. including sodium butyrate (SB) and suberoylanilide hydroxamic (SAHA), suppress the growth of prostate cancer cells in vitro Methylation-specific PCR (MS-PCR). MS-PCR was performed with bisulfite-treated genomic DNA from treated and untreated cells and in vivo. While the exact mechanisms underlying this growth grown in 100 mm plates. Genomic DNA was isolated using reagents inhibition have not been fully elucidated, it appears that HDACi from Stratagene (La Jolla, CA, USA) according to the induce the expression of several tumor suppressor genes, such manufacturer’s protocol and treated with bisulfite according to a as the cyclin-dependent kinase inhibitors (CDKI) p21 and p16 published protocol (12). MS-PCR was performed with primers (6-9), as well as genes whose products can induce specific for either methylated or bisulfite-modified unmethylated differentiation, such as retinoic acid receptor β2 (RARB2) (10). DNA. The PCR reactions were carried out in a Hybaid PCR Sprint These types of tumor suppressor genes are frequently silenced Thermal Cycler (Hybaid, Franklin, MA, USA). PCR amplifications without genomic DNA were performed as controls. Each PCR in many classes of tumors, including prostate cancer (11). This product was run on a 2% agarose gel, stained with ethidium suggests that exposure to HDACi may influence genes silenced bromide, and visualized under UV illumination. by DNA methylation, either independently of their DNA Total RNA was prepared from pelleted cells using Trizol reagent methylation or by altering their methylation, and thereby (Invitrogen) according to the manufacturer’s protocol. PCR was modulate the growth of tumor cells. performed with cDNA using primers specific for DNMTs 1, 3a, 3b We initiated this work to investigate: (i) whether HDACi and actin, as described below. PCR amplifications without DNA reverse the promoter methylation of silenced genes; (ii) were performed as controls. PCR products were also separated on a 2% agarose gel, stained with ethidium bromide, and visualized whether such promoter demethylation reverses the expression under UV illumination, for quality control. of silenced genes and, if so, (iii) whether HDACi regulate Real-time quantitative PCR was performed with the cDNA DNMT function by a signaling mechanism. We report that prepared as described above for quantitation of RARB2, p21 and p16 exposure to HDACi inhibits the activating phosphorylation transcript expression. The results were normalized with the of ERK, which then causes down-regulation of DNMT1. expression level of β-actin transcripts in each sample. The PCR was Suppression of DNMT1 in turn results in demethylation of performed in triplicate for each sample and the means are presented key tumor suppressor genes, such as RARB2, p21 and p16. with the standard deviations. Primers used for PCR are shown in Tables I-III. Specific repression of DNMT1 by small interfering RNA (siRNA) is sufficient to demethylate and depress expression Cell cycle analyses. For cell cycle analyses, cells were treated with of these tumor suppressor genes, and suppression of ERK SB or SAHA for the indicated times and stained with propidium activity by various means is sufficient to inhibit DNMT1 iodide (PI) as described elsewhere (13) and then analyzed for DNA levels. These studies thus elucidate a pathway in which ERK content by flow cytometry. activity, regulated by HDACi, lies upstream of DNMT1, and DNMT1 suppression, by repression of ERK activity, results siRNA knock-down. DNMT1, MEK1 and MEK2 siRNA Accell Smart in the demethylation of silenced genes. Pools and non-specific siRNAs were obtained from Dharmacon. LNCaP cells were transfected twice at 24 h intervals with siRNAs, according to the protocol provided by the manufacturer. Briefly, Materials
Load more

Recommended publications
  • Interplay Between Epigenetics and Metabolism in Oncogenesis: Mechanisms and Therapeutic Approaches
    OPEN Oncogene (2017) 36, 3359–3374 www.nature.com/onc REVIEW Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches CC Wong1, Y Qian2,3 and J Yu1 Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment. In this review, we summarized the recent discoveries linking epigenetics and metabolism and their underlying roles in tumorigenesis; and highlighted the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these abnormalities in cancer. Oncogene (2017) 36, 3359–3374; doi:10.1038/onc.2016.485; published online 16 January 2017 INTRODUCTION metabolic genes have also been identified as driver genes It has been appreciated since the early days of cancer research mutated in some cancers, such as isocitrate dehydrogenase 1 16 17 that the metabolic profiles of tumor cells differ significantly from and 2 (IDH1/2) in gliomas and acute myeloid leukemia (AML), 18 normal cells. Cancer cells have high metabolic demands and they succinate dehydrogenase (SDH) in paragangliomas and fuma- utilize nutrients with an altered metabolic program to support rate hydratase (FH) in hereditary leiomyomatosis and renal cell 19 their high proliferative rates and adapt to the hostile tumor cancer (HLRCC).
    [Show full text]
  • The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc Oncogenesis
    The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc oncogenesis By Yuting Sun This thesis is submitted in fulfilment of the requirements for the degree of Doctor of Philosophy at the University of New South Wales Children’s Cancer Institute Australia for Medical Research School of Women’s and Children’s Health, Faculty of Medicine University of New South Wales Australia August 2014 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Sun First name: Yuting Other name/s: Abbreviation for degree as given in the University calendar: PhD School : School of·Women's and Children's Health Faculty: Faculty of Medicine Title: The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc oncogenesis. Abstract 350 words maximum: (PLEASE TYPE) N-Myc Induces neuroblastoma by regulating the expression of target genes and proteins, and N-Myc protein is degraded by Fbxw7 and NEDD4 and stabilized by Aurora A. The class lla histone deacetylase HDAC5 suppresses gene transcription, and blocks myoblast and leukaemia cell differentiation. While histone H3 lysine 4 (H3K4) trimethylation at target gene promoters is a pre-requisite for Myc· induced transcriptional activation, WDRS, as a histone H3K4 methyltransferase presenter, is required for H3K4 methylation and transcriptional activation mediated by a histone H3K4 methyltransferase complex. Here, I investigated the roles of HDAC5 and WDR5 in N-Myc overexpressing neuroblastoma. I have found that N-Myc upregulates HDAC5 protein expression, and that HDAC5 represses NEDD4 gene expression, increases Aurora A gene expression and consequently upregulates N-Myc protein expression in neuroblastoma cells.
    [Show full text]
  • Structural and Functional Coordination of DNA and Histone Methylation
    Structural and Functional Coordination of DNA and Histone Methylation Xiaodong Cheng Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322 Correspondence: [email protected] SUMMARY One of the most fundamental questions in the control of gene expression in mammals is how epigenetic methylation patterns of DNA and histones are established, erased, and recognized. This central process in controlling gene expression includes coordinated covalent modifications of DNA and its associated histones. This article focuses on structural aspects of enzymatic activities of histone (arginine and lysine) methylation and demethylation and functional links between the methylation status of the DNA and histones. An interconnected network of methyltransferases, demethylases, and accessory proteins is responsible for changing or maintaining the modification status of specific regions of chromatin. Outline 1 Histone methylation and demethylation 4 Summary 2 DNA methylation References 3 Interplay between DNA methylation and histone modification Editors: C. David Allis, Marie-Laure Caparros, Thomas Jenuwein, and Danny Reinberg Additional Perspectives on Epigenetics available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a018747 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a018747 1 X. Cheng OVERVIEW All cells face the problem of controlling the amounts and articles by Becker and Workman 2013; Allis et al. 2014; timing of expression of their
    [Show full text]
  • Euchromatin Histone Methyltransferase II (EHMT2) Regulates the Expression of Ras-Related GTP Binding C (RRAGC) Protein
    BMB Rep. 2020; 53(11): 576-581 BMB www.bmbreports.org Reports Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein Supyong Hwang1, Soyoung Kim1, Kyungkon Kim1,2,3, Jeonghun Yeom2, Sojung Park1 & Inki Kim1,2,3,* 1Biomedical Research Center, ASAN Institute for Life Sciences, ASAN Medical Center, Seoul 05505, 2Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, ASAN Medical Center, Seoul 05505, 3Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea Dimethylation of the histone H3 protein at lysine residue 9 INTRODUCTION (H3K9) is mediated by euchromatin histone methyltransferase II (EHMT2) and results in transcriptional repression of target Epigenetic modifications are gene regulatory mechanisms that genes. Recently, chemical inhibition of EHMT2 was shown to are independent of changes in DNA sequences (1). This mode induce various physiological outcomes, including endoplasmic of gene regulation can be achieved by means of histone and reticulum stress-associated genes transcription in cancer cells. DNA modifications, such as methylation and acetylation (1). To identify genes that are transcriptionally repressed by EHMT2 Among these, methylation at lysine residues 4 (H3K4) and 36 during apoptosis, and cell stress responses, we screened genes (H3K36) of histone H3 are hallmarks of transcriptional acti- that are upregulated by BIX-01294, a chemical inhibitor of vation, whereas methylation of histone H3 residues at lysines EHMT2. RNA sequencing analyses revealed 77 genes that were 9 (H3K9) and 27 (H3K27) leads to repression (2). Methylation upregulated by BIX-01294 in all four hepatic cell carcinoma of histones is accomplished by histone methyltransferases (HMTs) (HCC) cell lines.
    [Show full text]
  • DNMT1 Gene DNA Methyltransferase 1
    DNMT1 gene DNA methyltransferase 1 Normal Function The DNMT1 gene provides instructions for making an enzyme called DNA methyltransferase 1. This enzyme is involved in DNA methylation, which is the addition of methyl groups, consisting of one carbon atom and three hydrogen atoms, to DNA molecules. In particular, the enzyme helps add methyl groups to DNA building blocks ( nucleotides) called cytosines. DNA methylation is important in many cellular functions. These include determining whether the instructions in a particular segment of DNA are carried out or suppressed ( gene silencing), regulating reactions involving proteins and fats (lipids), and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters). DNA methyltransferase 1 is active in the adult nervous system. Although its specific function is not well understood, the enzyme may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of neurons to move (migrate) and connect with each other, and neuron survival. Health Conditions Related to Genetic Changes Autosomal dominant cerebellar ataxia, deafness, and narcolepsy At least four DNMT1 gene mutations have been identified in people with a nervous system disorder called autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN). Features of this disorder include difficulty coordinating movements (ataxia), hearing loss caused by abnormalities of the inner ear (sensorineural deafness), and excessive daytime sleepiness (narcolepsy). Cognitive decline occurs as the disorder progresses. Numbness, tingling, or pain in the arms and legs (sensory neuropathy) can also occur. Affected individuals usually survive into their forties or fifties. The DNMT1 gene mutations associated with this disorder affect a region of the DNA methyltransferase 1 enzyme, known as the targeting sequence, that helps direct the methylation process to the correct segments of DNA.
    [Show full text]
  • The Histone Deacetylase HDA15 Interacts with MAC3A and MAC3B to Regulate Intron
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386672; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 The histone deacetylase HDA15 interacts with MAC3A and MAC3B to regulate intron 2 retention of ABA-responsive genes 3 4 Yi-Tsung Tu1#, Chia-Yang Chen1#, Yi-Sui Huang1, Ming-Ren Yen2, Jo-Wei Allison Hsieh2,3, 5 Pao-Yang Chen2,3*and Keqiang Wu1* 6 7 1Institute of Plant Biology, National Taiwan University, Taipei 10617, Taiwan 8 2 Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan 9 3 Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan 10 University, Taipei, Taiwan 11 12 # These authors contributed equally to this work. 13 * Corresponding authors: Keqiang Wu ([email protected], +886-2-3366-4546) and Pao-Yang 14 Chen ([email protected], +886-2-2787-1140) 15 16 Short title: HDA15 and MAC3A/MAC3B coregulate intron retention 17 One sentence summary: HDA15 and MAC3A/MAC3B coregulate intron retention and reduce 18 the histone acetylation level of the genomic regions near ABA-responsive retained introns. 19 20 The author responsible for distribution of materials integral to the findings presented in this 21 article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) 22 is: Keqiang Wu ([email protected]) 23 24 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386672; this version posted November 17, 2020.
    [Show full text]
  • Distinct Contributions of DNA Methylation and Histone Acetylation to the Genomic Occupancy of Transcription Factors
    Downloaded from genome.cshlp.org on October 8, 2021 - Published by Cold Spring Harbor Laboratory Press Research Distinct contributions of DNA methylation and histone acetylation to the genomic occupancy of transcription factors Martin Cusack,1 Hamish W. King,2 Paolo Spingardi,1 Benedikt M. Kessler,3 Robert J. Klose,2 and Skirmantas Kriaucionis1 1Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, United Kingdom; 2Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom; 3Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, United Kingdom Epigenetic modifications on chromatin play important roles in regulating gene expression. Although chromatin states are often governed by multilayered structure, how individual pathways contribute to gene expression remains poorly under- stood. For example, DNA methylation is known to regulate transcription factor binding but also to recruit methyl-CpG binding proteins that affect chromatin structure through the activity of histone deacetylase complexes (HDACs). Both of these mechanisms can potentially affect gene expression, but the importance of each, and whether these activities are inte- grated to achieve appropriate gene regulation, remains largely unknown. To address this important question, we measured gene expression, chromatin accessibility, and transcription factor occupancy in wild-type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. We observe widespread increases in chromatin accessibility at ret- rotransposons when HDACs are inhibited, and this is magnified when cells also lack DNA methylation. A subset of these elements has elevated binding of the YY1 and GABPA transcription factors and increased expression. The pronounced ad- ditive effect of HDAC inhibition in DNA methylation–deficient cells demonstrates that DNA methylation and histone deacetylation act largely independently to suppress transcription factor binding and gene expression.
    [Show full text]
  • From 1957 to Nowadays: a Brief History of Epigenetics
    International Journal of Molecular Sciences Review From 1957 to Nowadays: A Brief History of Epigenetics Paul Peixoto 1,2, Pierre-François Cartron 3,4,5,6,7,8, Aurélien A. Serandour 3,4,6,7,8 and Eric Hervouet 1,2,9,* 1 Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; [email protected] 2 EPIGENEXP Platform, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France 3 CRCINA, INSERM, Université de Nantes, 44000 Nantes, France; [email protected] (P.-F.C.); [email protected] (A.A.S.) 4 Equipe Apoptose et Progression Tumorale, LaBCT, Institut de Cancérologie de l’Ouest, 44805 Saint Herblain, France 5 Cancéropole Grand-Ouest, Réseau Niches et Epigénétique des Tumeurs (NET), 44000 Nantes, France 6 EpiSAVMEN Network (Région Pays de la Loire), 44000 Nantes, France 7 LabEX IGO, Université de Nantes, 44000 Nantes, France 8 Ecole Centrale Nantes, 44300 Nantes, France 9 DImaCell Platform, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France * Correspondence: [email protected] Received: 9 September 2020; Accepted: 13 October 2020; Published: 14 October 2020 Abstract: Due to the spectacular number of studies focusing on epigenetics in the last few decades, and particularly for the last few years, the availability of a chronology of epigenetics appears essential. Indeed, our review places epigenetic events and the identification of the main epigenetic writers, readers and erasers on a historic scale. This review helps to understand the increasing knowledge in molecular and cellular biology, the development of new biochemical techniques and advances in epigenetics and, more importantly, the roles played by epigenetics in many physiological and pathological situations.
    [Show full text]
  • The Role of B-Vitamins – Gene Interactions in Colorectal Carcinogenesis a Molecular Epidemiological Approach
    THE ROLE OF B-VITAMINS – GENE INTERACTIONS IN COLORECTAL CARCINOGENESIS A MOLECULAR EPIDEMIOLOGICAL APPROACH Promotor Prof. dr. ir. F.J. Kok Hoogleraar Voeding en Gezondheid Wageningen Universiteit Co-promotoren Dr. ir. E. Kampman Universitair Hoofddocent, sectie Humane Voeding Wageningen Universiteit Dr. J. Keijer Hoofd Food Bioactives Group RIKILT – Instituut voor Voedselveiligheid Promotiecommissie Prof. dr. J. Mathers University of Newcastle Upon Tyne, United Kingdom Prof. dr. G.A. Meijer VU Medisch Centrum, Amsterdam Dr. ir. P. Verhoef Wageningen Centre for Food Sciences Prof. dr. S.C. de Vries Wageningen Universiteit Dit onderzoek is uitgevoerd binnen de onderzoeksschool VLAG. THE ROLE OF B-VITAMINS – GENE INTERACTIONS IN COLORECTAL CARCINOGENESIS A MOLECULAR EPIDEMIOLOGICAL APPROACH Maureen van den Donk Proefschrift ter verkrijging van de graad van doctor op gezag van de rector magnificus van Wageningen Universiteit, Prof. dr. M.J. Kropff, in het openbaar te verdedigen op dinsdag 13 december 2005 des namiddags te half twee in de Aula Maureen van den Donk The role of B-vitamins – gene interactions in colorectal carcinogenesis – A molecular epidemiological approach Thesis Wageningen University – With references – With summary in Dutch ISBN 90-8504-328-X ABSTRACT The role of B-vitamins–gene interactions in colorectal carcinogenesis – A molecular epidemiological approach PhD thesis by Maureen van den Donk, Division of Human Nutrition, Wageningen University, The Netherlands, December 13, 2005. Folate deficiency can affect DNA methylation and DNA synthesis. Both factors may be operative in colorectal carcinogenesis. Many enzymes, like methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MTR), and serine hydroxymethyltransferase (SHMT), are needed for conversions in folate metabolism.
    [Show full text]
  • Pan-Histone Deacetylase Inhibitors Regulate Signaling Pathways
    Majumdar et al. BMC Genomics 2012, 13:709 http://www.biomedcentral.com/1471-2164/13/709 RESEARCH ARTICLE Open Access Pan-histone deacetylase inhibitors regulate signaling pathways involved in proliferative and pro-inflammatory mechanisms in H9c2 cells Gipsy Majumdar1, Piyatilake Adris1, Neha Bhargava1, Hao Chen2 and Rajendra Raghow1,2* Abstract Background: We have shown previously that pan-HDAC inhibitors (HDACIs) m-carboxycinnamic acid bis-hydroxamide (CBHA) and trichostatin A (TSA) attenuated cardiac hypertrophy in BALB/c mice by inducing hyper-acetylation of cardiac chromatin that was accompanied by suppression of pro-inflammatory gene networks. However, it was not feasible to determine the precise contribution of the myocytes- and non-myocytes to HDACI-induced gene expression in the intact heart. Therefore, the current study was undertaken with a primary goal of elucidating temporal changes in the transcriptomes of cardiac myocytes exposed to CBHA and TSA. Results: We incubated H9c2 cardiac myocytes in growth medium containing either of the two HDACIs for 6h and 24h and analyzed changes in gene expression using Illumina microarrays. H9c2 cells exposed to TSA for 6h and 24h led to differential expression of 468 and 231 genes, respectively. In contrast, cardiac myocytes incubated with CBHA for 6h and 24h elicited differential expression of 768 and 999 genes, respectively. We analyzed CBHA- and TSA-induced differentially expressed genes by Ingenuity Pathway (IPA), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Core_TF programs and discovered that CBHA and TSA impinged on several common gene networks. Thus, both HDACIs induced a repertoire of signaling kinases (PTEN-PI3K-AKT and MAPK) and transcription factors (Myc, p53, NFkB and HNF4A) representing canonical TGFβ, TNF-α, IFNγ and IL-6 specific networks.
    [Show full text]
  • Histone Deacetylase Inhibitors Synergizes with Catalytic Inhibitors of EZH2 to Exhibit Anti-Tumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type
    Author Manuscript Published OnlineFirst on September 19, 2018; DOI: 10.1158/1535-7163.MCT-18-0348 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Histone deacetylase inhibitors synergizes with catalytic inhibitors of EZH2 to exhibit anti- tumor activity in small cell carcinoma of the ovary, hypercalcemic type Yemin Wang1,2,*, Shary Yuting Chen1,2, Shane Colborne3, Galen Lambert2, Chae Young Shin2, Nancy Dos Santos4, Krystal A. Orlando5, Jessica D. Lang6, William P.D. Hendricks6, Marcel B. Bally4, Anthony N. Karnezis1,2, Ralf Hass7, T. Michael Underhill8, Gregg B. Morin3,9, Jeffrey M. Trent6, Bernard E. Weissman5, David G. Huntsman1,2,10,* 1Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada 2Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada. 3Michael Smith Genome Science Centre, British Columbia Cancer Agency, Vancouver, BC, Canada. 4Department of Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, BC, Canada. 5Department of Pathology and Laboratory Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. 6Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. 7Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany. 8Department of Cellular and Physiological Sciences and Biomedical Research Centre, University 1 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 19, 2018; DOI: 10.1158/1535-7163.MCT-18-0348 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Stress-Related Methylation of the Catechol-O-Methyltransferase Val158 Allele Predicts Human Prefrontal Cognition and Activity
    6692 • The Journal of Neuroscience, May 4, 2011 • 31(18):6692–6698 Behavioral/Systems/Cognitive Stress-Related Methylation of the Catechol-O-Methyltransferase Val158 Allele Predicts Human Prefrontal Cognition and Activity Gianluca Ursini,1,2 Valentina Bollati,3,4 Leonardo Fazio,1 Annamaria Porcelli,1 Luisa Iacovelli,5 Assia Catalani,5 Lorenzo Sinibaldi,2 Barbara Gelao,1 Raffaella Romano,1 Antonio Rampino,1 Paolo Taurisano,1 Marina Mancini,1 Annabella Di Giorgio,1,6 Teresa Popolizio,6 Andrea Baccarelli,3,4,7 Antonio De Blasi,8 Giuseppe Blasi,1 and Alessandro Bertolino1,6 1Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University “Aldo Moro”, 71024 Bari, Italy, 2Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy, 3Center for Molecular and Genetic Epidemiology, Department of Environmental and Occupational Health, University of Milan, Milan, Italy, 4Istituto Di Ricovero e Cura a Carattere Scientifico Maggiore Hospital, Mangiagalli and Regina Elena Foundation, 20122 Milan, Italy, 5Department of Physiology and Pharmacology “V. Erspamer”, University of Rome “Sapienza”, 00185 Rome, Italy, 6Department of Neuroradiology, IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy, 7Exposure, Epidemiology, and Risk Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115- 6018, and 8Department of Molecular Medicine, University of Rome “Sapienza”, 00185 Rome, Italy DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val 158 allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide.
    [Show full text]