Resveratrol inhibits the proliferation of estrogen receptor-positive breast cancer cells by suppressing EZH2 through the modulation of ERK1/2 signaling

Cell Biol Toxicol. 2019 Oct;35(5):445-456. doi: 10.1007/s10565-019-09471-x. Epub 2019 Apr 2.


Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in breast cancer and plays an important role in maintaining the cell proliferative capacity. However, the mechanisms underlying the transcriptional regulation of EZH2 in estrogen receptor (ER)-positive breast cancer cells remain unclear. The antitumor effects of resveratrol have been reported. However, whether EZH2 was involved in these effects needs further exploration. Here, we showed that EZH2 is required for estrogen-induced cell proliferation in ER-positive breast cancer. Exposure to 17β-estradiol (E2) upregulated EZH2 via ERα signaling, and this effect was blocked by U0126, a MEK inhibiter. Resveratrol inhibited the proliferation and colony formation in ER-positive breast cancer cells and downregulated EZH2 through inhibition of phospho-ERK1/2. These findings indicated that ERK1/2 and ER signaling-mediated EZH2 upregulation is crucial for the proliferation of ER-positive breast cancer cells. The suppression of EZH2 expression by ERK1/2 dephosphorylation is important for the antiproliferative activities of resveratrol against ER-positive breast cancer cells.

Keywords: EZH2; Estrogen receptor; Phospho-ERK1/2; Proliferation; Resveratrol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Resveratrol / metabolism
  • Resveratrol / therapeutic use*
  • Signal Transduction / drug effects


  • Butadienes
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • Nitriles
  • U 0126
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 3
  • Resveratrol