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

Katarzyna Lubecka, Lucinda Kurzava, Kirsty Flower, Hannah Buvala, Hao Zhang, Dorothy Teegarden, Ignacio Camarillo, Matthew Suderman, Shihuan Kuang, Ourania Andrisani, James M. Flanagan, Barbara Stefanska*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

36 Citations (Scopus)
297 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)656-668
Number of pages13
JournalCarcinogenesis
Volume37
Issue number7
Early online date28 Apr 2016
DOIs
Publication statusPublished - 1 Jul 2016

Keywords

  • signal transduction
  • transcription
  • genetic
  • cancer
  • brachial plexus neuritis
  • chromatin
  • dna methylation
  • down-regulation
  • genes
  • genome
  • histones
  • methylation
  • neoplasm metastasis
  • transcription factor
  • breast cancer
  • carcinogenesis
  • epigenetics
  • breast cancer cell
  • candidate disease gene
  • enhancer of transcription

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