title: Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity.
abstract: DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Following Illumina 450K, genome-wide DNA methylation analysis reveals that stilbenoids alter DNA methylation patterns in breast cancer cells. On average, 75% of differentially methylated genes have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. MAML2, a coactivator of NOTCH targets, is methylated at the enhancer region and transcriptionally silenced in response to stilbenoids, possibly explaining the downregulation of NOTCH target genes. The increased DNA methylation at MAML2 enhancer coincides with increased occupancy of repressive histone marks and decrease in activating marks. This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. Our results deliver a novel insight into epigenetic regulation of oncogenic signals in cancer and provide support for epigenetic-targeting strategies as an effective anticancer approach.
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Lubecka
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Kurzava
authors.affiliation: Epigenetic Unit, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Flower
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Buvala
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA Purdue University Center for Cancer Research, West Lafayette, IN, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Teegarden
authors.affiliation: Purdue University Center for Cancer Research, West Lafayette, IN, USA Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Camarillo
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Suderman
authors.affiliation: Purdue University Center for Cancer Research, West Lafayette, IN, USA Department of Animal Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA Purdue University Center for Cancer Research, West Lafayette, IN, USA.
authors.forename: Ourania
authors.initials: O
authors.lastname: Andrisani
authors.affiliation: Epigenetic Unit, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Flanagan
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA Purdue University Center for Cancer Research, West Lafayette, IN, USA bstefanska@purdue.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Stefanska
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D027702:Organic Cation Transporter 1 / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch / Q000235:genetics; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000008:administration & dosage; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D002843:Chromatin; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D027702:Organic Cation Transporter 1; D051880:Receptors, Notch; D000077185:Resveratrol; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C471297:MAML2 protein, human; C107773:pterostilbene