Stilbenoid-Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

Mol Nutr Food Res. 2019 Oct;63(19):e1801386. doi: 10.1002/mnfr.201801386. Epub 2019 Jul 31.


Scope: Loci-specific increase in DNA methylation occurs in cancer and may underlie gene silencing. It is investigated whether dietary stilbenoids, resveratrol, and pterostilbene exert time-dependent effects on DNA methylation patterns and specifically methylation-silenced tumor suppressor genes in breast cancer cells.

Methods and results: Following genome-wide DNA methylation analysis with Illumina-450K, changes characteristic of early and late response to stilbenoids are identified. Interestingly, often the same genes but at different CpG loci, the same gene families, or the same functional gene categories are affected. CpG loci that lose methylation in exposed cells correspond to genes functionally associated with cancer suppression. There is a group of genes, including SEMA3A, at which the magnitude of hypomethylation in response to stilbenoids rises with increasing invasive potential of cancer cells. Decreased DNA methylation at SEMA3A promoter and concomitant gene upregulation coincide with increased occupancy of active histone marks. Open chromatin upon exposure to stilbenoids may be linked to decreased DNMT3A binding followed by increased NF1C transcription factor occupancy. Sequestration of DNMT3A is possibly a result of stilbenoid-mediated increase in SALL3 expression, which was previously shown to bind and inhibit DNMT3A activity.

Conclusions: The findings define mechanistic players in stilbenoid-mediated epigenetic reactivation of genes suppressing cancer.

Keywords: DNA methylation; DNMT3A; NF1C; breast cancer; stilbenoids; tumor suppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA / metabolism
  • DNA Methylation / drug effects
  • DNA Methyltransferase 3A
  • Epigenesis, Genetic / drug effects*
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Gene Silencing / drug effects
  • Homeodomain Proteins / genetics
  • Humans
  • NFI Transcription Factors / metabolism*
  • Neoplasm Invasiveness / prevention & control
  • Promoter Regions, Genetic / genetics
  • Resveratrol / pharmacology
  • Semaphorin-3A / genetics*
  • Semaphorin-3A / physiology
  • Stilbenes / pharmacology*
  • Transcription Factors / genetics


  • DNMT3A protein, human
  • Homeodomain Proteins
  • NFI Transcription Factors
  • SALL3 protein, human
  • Semaphorin-3A
  • Stilbenes
  • Transcription Factors
  • transcription factor nuclear factor 1
  • pterostilbene
  • DNA
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • Resveratrol