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

PLoS One. 2016 Jun 29;11(6):e0157866. doi: 10.1371/journal.pone.0157866. eCollection 2016.

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.

MeSH terms

  • Anticarcinogenic Agents / therapeutic use*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / prevention & control*
  • Cell Line, Tumor
  • CpG Islands
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genome-Wide Association Study
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Resveratrol
  • Stilbenes / therapeutic use*

Substances

  • Anticarcinogenic Agents
  • Stilbenes
  • Resveratrol

Grant support

The authors acknowledge CONACYT SALUD for support of this work (233370 and 222335 grants). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Rubiceli Medina was supported by a CONACYT fellowship. The authors also thank Universidad Autonoma de la Ciudad de Mexico (UACM) for support.