Resveratrol up-regulates ATP2A3 gene expression in breast cancer cell lines through epigenetic mechanisms

Int J Biochem Cell Biol. 2019 Aug;113:37-47. doi: 10.1016/j.biocel.2019.05.020. Epub 2019 Jun 4.

Abstract

Resveratrol (RSV) is a phytoestrogen which has been related to chemoprevention of several types of cancer. In this work, we show up to a 6-fold increased expression of ATP2A3 gene induced by RSV that triggers apoptosis and changes of intracellular Ca2+ management in MCF-7 and MDA-MB-231 breast cancer cell lines. We explored epigenetic mechanisms for that RSV-induced ATP2A3 up-regulation. The results indicate that RSV-induced ATP2A3 up-regulation correlates with about 50% of reduced HDAC activity and reduced nuclear HDAC2 expression and occupancy on ATP2A3 promoter, increasing the global acetylation of histone H3 and the enrichment of histone mark H3K27Ac on the proximal promoter of the ATP2A3 gene in MDA-MB-231 cells. We also quantified HAT activity, finding that it can be boosted with RSV treatment; however, pharmacological inhibition of p300, one of the main HATs, did not have significant effects in RSV-mediated ATP2A3 gene expression. Additionally, DNMT activity was also reduced in cells treated with RSV, as well as the expression of Methyl-DNA binding proteins MeCP2 and MBD2. However, analysis of the methylation pattern of ATP2A3 gene promoter showed un-methylated promoter in both cell lines. Taken together, the results of this work help to explain, at the molecular level, how ATP2A3 gene is regulated in breast cancer cells, and the benefits of RSV intake observed in epidemiological data, studies with animals, and in vitro models.

Keywords: Breast cancer; DNA methylation; Deacetylation; Epigenetics; Resveratrol; SERCA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Calcium / metabolism
  • Cell Line, Tumor
  • CpG Islands
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Histone Deacetylase 2 / antagonists & inhibitors
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism
  • Humans
  • MCF-7 Cells
  • Promoter Regions, Genetic
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / biosynthesis
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Up-Regulation / drug effects

Substances

  • Antioxidants
  • Histone Deacetylase Inhibitors
  • DNA (Cytosine-5-)-Methyltransferases
  • HDAC2 protein, human
  • Histone Deacetylase 2
  • Histone Deacetylases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A3 protein, human
  • Calcium