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

SCOPE: Loci-specific increase in DNA methylation occurs in cancer and may underlie gene silencing. We investigate 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, we identified changes characteristic of early and late response to stilbenoids. Interestingly, often the same genes but at different CpG loci, the same gene families or the same functional gene categories were affected. CpG loci that lost methylation in exposed cells corresponded to genes functionally associated with cancer suppression. There was 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 coincided with increased occupancy of active histone marks. Open chromatin upon exposure to stilbenoids might 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: Our findings define mechanistic players in stilbenoid-mediated epigenetic reactivation of genes suppressing cancer.