Pterostilbene Changes Epigenetic Marks at Enhancer Regions of Oncogenes in Breast Cancer Cells

Abstract

Epigenetic aberrations are linked to sporadic breast cancer. Interestingly, certain dietary polyphenols with anti-cancer effects, such as pterostilbene (PTS), have been shown to regulate gene expression by altering epigenetic patterns. Our group has proposed the involvement of DNA methylation and DNA methyltransferase 3B (DNMT3B) as vital players in PTS-mediated suppression of candidate oncogenes and suggested a role of enhancers as target regions. In the present study, we assess a genome-wide impact of PTS on epigenetic marks at enhancers in highly invasive MCF10CA1a breast cancer cells. Following chromatin immunoprecipitation (ChIP)-sequencing in MCF10CA1a cells treated with 7 μM PTS for 9 days, we discovered that PTS leads to increased binding of DNMT3B at enhancers of 77 genes, and 17 of those genes display an overlapping decrease in the occupancy of trimethylation at lysine 36 of histone 3 (H3K36me3), a mark of active enhancers. We selected two genes, PITPNC1 and LINC00910, and found that their enhancers are hypermethylated in response to PTS. These changes coincided with the downregulation of gene expression. Of importance, we showed that 6 out of 17 target enhancers, including PITPNC1 and LINC00910, are bound by an oncogenic transcription factor OCT1 in MCF10CA1a cells. Indeed, the six enhancers corresponded to genes with established or putative cancer-driving functions. PTS led to a decrease in OCT1 binding at those enhancers, and OCT1 depletion resulted in PITPNC1 and LINC00910 downregulation, further demonstrating a role for OCT1 in transcriptional regulation. Our findings provide novel evidence for the epigenetic regulation of enhancer regions by dietary polyphenols in breast cancer cells.

Epigenetic Effects of Resveratrol on Oncogenic Signaling in Breast Cancer

“…Importantly, our previous studies demonstrated that 80% of RSV hypermethylated target genes contain a sequence corresponding to the OCT1 response element, which we quantitatively validated for a set of genes [ 14 , 15 , 16 ]. Using chromatin immunoprecipitation (ChIP), we experimentally confirmed OCT1 binding to GLI2 and WNT4 enhancer regions in control cells ( Figure 4 C , D).…”

“…Interestingly, naturally derived compounds have been shown by us and others to modify the epigenome and bring about profound phenotypic changes at non-toxic doses [ 14 , 15 , 16 ]. Our previous findings demonstrated that polyphenols from the stilbenoid class, including resveratrol (RSV), lead to increased levels of DNA methylation at regulatory regions of hundreds of oncogenes in breast cancer, thereby decreasing their transcriptional activities [ 16 ].…”

Pterostilbene alleviates abdominal aortic aneurysm via inhibiting macrophage pyroptosis by activating the miR-146a-5p/TRAF6 axis

“…54,55 Previous studies have demonstrated that PTE protects against gastric and breast cancer. 56,57 Moreover, PTE attenuates atherosclerosis by reducing vascular inflammation. However, the role of PTE in AAA remains poorly understood.…”

Oxidative Stress: The Role of Antioxidant Phytochemicals in the Prevention and Treatment of Diseases

“…Pterostilbene (PTS), a stilbenoid polyphenol with high bioavailability, shows promise in breast cancer cells by inducing epigenetic silencing of oncogenes. Harandi-Zadeh et al’s experimental study provides new insights into the potential anticancer actions of PTS [ 62 ].…”