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Epigenetic mechanisms of anti-cancer effects of dietary stilbenoids Beetch, Megan


Epigenetics refers to control of gene expression without changes to the underlying DNA sequence. DNA methylation, a dynamic epigenetic modification responsive to environmental factors, underlies genomic instability, silencing of tumor suppressor genes (TSGs), and activation of genes driving cancer development. Reversing DNA methylation patterns established during carcinogenesis constitutes a promising anti-cancer strategy. Interestingly, certain dietary polyphenols, such as stilbenoids abundantly found in grapes and blueberries, have been shown to exert anti-cancer effects through epigenetic gene regulation. The overarching objective of my research is to understand epigenetic mechanisms of stilbenoids’ anti-cancer effects. We hypothesize that dietary stilbenoids, resveratrol (RSV) and pterostilbene (PTS), modulate DNA methylation patterns and thereby gene transcription via modifying expression and activity of epigenetic enzymes such as DNA methyltransferases (DNMTs) and transcriptional machinery such as transcription factors (TFs). Stilbenoid-induced changes in DNA methylation and transcriptional machinery could, in turn, lead to reactivation of methylation-silenced TSGs and downregulation of epigenetically-activated oncogenes leading to reduced cancer development. Upon treatment with RSV (15 μM, 9 days), DNA methylation levels in MCF10CA1a breast cancer cells were altered as assessed by genome-wide DNA methylation analysis. Hypermethylated CpG sites corresponded to genes predominantly associated with oncogenic functions, whereas hypomethylated sites were located in genes with potential tumor suppressor roles. Changes in methylation and expression of candidate oncogenes and TSGs were examined using pyrosequencing and qPCR, respectively, upon treatment with RSV or PTS. Further, chromatin immunoprecipitation (ChIP) sequencing assessed DNA binding events, including occupancy of DNMTs and TFs at stilbenoid-mediated differentially methylated sites. Specific putative roles for de novo DNMTs in mediating changes in DNA methylation patterns upon exposure to stilbenoids were established. Based on our findings in cell lines, we turned to an in vivo model of methyl donor deficiency to assess the contribution of methyl donors, another important factor for maintaining normal DNA methylation patterns, to carcinogenesis. Collectively, these findings provide evidence that dietary stilbenoids may exert their anti-cancer effects, at least partially, by impacting DNA methylation machinery, and as a result, this line of evidence has potential to be used to develop novel anti-cancer approaches.

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