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Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity

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Title: Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity
Author(s): Lubecka, K
Kurzava, L
Flower, K
Buvala, H
Zhang, H
Teegarden, D
Camarillo, I
Suderman, M
Kuang, S
Andrisani, O
Flanagan, JM
Stefanska, B
Item Type: Journal Article
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.
Publication Date: 28-Apr-2016
Date of Acceptance: 15-Apr-2016
URI: http://hdl.handle.net/10044/1/34646
DOI: http://dx.doi.org/10.1093/carcin/bgw048
ISSN: 1460-2180
Publisher: Oxford University Press
Start Page: 656
End Page: 668
Journal / Book Title: Carcinogenesis
Volume: 37
Issue: 7
Copyright Statement: © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Breast Cancer Now
Breast Cancer Campaign
Funder's Grant Number: 2009MaySF03
WSCC_P33227
Keywords: Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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