Methylation Landscape of Human Breast Cancer Cells in Response to Dietary Compound Resveratrol

Abstract

Aberrant DNA methylation is a frequent epigenetic alteration in cancer cells that has emerged as a pivotal mechanism for tumorigenesis. Accordingly, novel therapies targeting the epigenome are being explored with the aim to restore normal DNA methylation patterns on oncogenes and tumor suppressor genes. A limited number of studies indicate that dietary compound resveratrol modulates DNA methylation of several cancer-related genes; however a complete view of changes in methylome by resveratrol has not been reported yet. In this study we performed a genome-wide survey of DNA methylation signatures in triple negative breast cancer cells exposed to resveratrol. Our data showed that resveratrol treatment for 24 h and 48 h decreased gene promoter hypermethylation and increased DNA hypomethylation. Of 2476 hypermethylated genes in control cells, 1,459 and 1,547 were differentially hypomethylated after 24 h and 48 h, respectively. Remarkably, resveratrol did not induce widespread non-specific DNA hyper- or hypomethylation as changes in methylation were found in only 12.5% of 27,728 CpG loci. Moreover, resveratrol restores the hypomethylated and hypermethylated status of key tumor suppressor genes and oncogenes, respectively. Importantly, the integrative analysis of methylome and transcriptome profiles in response to resveratrol showed that methylation alterations were concordant with changes in mRNA expression. Our findings reveal for the first time the impact of resveratrol on the methylome of breast cancer cells and identify novel potential targets for epigenetic therapy. We propose that resveratrol may be considered as a dietary epidrug as it may exert its anti-tumor activities by modifying the methylation status of cancer -related genes which deserves further in vivo characterization.

Cadherins Associate with Distinct Stem Cell-Related Transcription Factors to Coordinate the Maintenance of Stemness in Triple-Negative Breast Cancer

“…As shown in Table 6, multiple drugs were identified that had a significantly anticorrelating gene pattern to that induced by CDH2/4/6/17. For instance, resveratrol and its derivatives had been reported to exhibit anticancer activity in TNBC cells possibly through interfering with epigenetic regulation [53, 54]. Thus, our findings provided additional evidence to support the claim that the affected pathways were induced by CDH2/4/6/17 and revealed that the perturbagens predicted here might be used to target TNBC with the alterations of CDH2/4/6/17-SC-TFs axis.…”

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

“…Similar findings have been reported in trials examining the ability of resveratrol to reduce homocysteine levels. Resveratrol significantly decreased serum levels of homocysteine in rats on a methionine-rich diet [ 291 , 292 ], and preferentially affected the methylation status of cancer cells [ 292 , 293 , 294 ]. However, despite extensive trials, resveratrol failed to inhibit aging-associated pathologies or extend the lifespan in mammals [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-Met signaling pathway

“…Resveratrol, a natural product found in red grapes and wine, is one of the most common dietary flavonoids. Except antioxidant and anti-inflammatory effect as reported, recent studies have demonstrated that resveratrol exerted antitumor effects on a panel of human cancers, such as breast (18), colon (19), ovarian (20), lung (21) and prostate cancer (22). Mechanism investigation manifested that multiple signaling pathways and mechanisms are involved in the antitumor activity of resveratrol, including suppression of various protein kinases, such as Akt, ERK and EGFR, induction of cell cycle arrest or apoptosis, and inhibition of cell migration and metastasis (23).…”