VEGFA activates an epigenetic pathway upregulating ovarian cancer-initiating cells

EMBO Mol Med. 2017 Mar;9(3):304-318. doi: 10.15252/emmm.201606840.

Abstract

The angiogenic factor, VEGFA, is a therapeutic target in ovarian cancer (OVCA). VEGFA can also stimulate stem-like cells in certain cancers, but mechanisms thereof are poorly understood. Here, we show that VEGFA mediates stem cell actions in primary human OVCA culture and OVCA lines via VEGFR2-dependent Src activation to upregulate Bmi1, tumor spheres, and ALDH1 activity. The VEGFA-mediated increase in spheres was abrogated by Src inhibition or SRC knockdown. VEGFA stimulated sphere formation only in the ALDH1+ subpopulation and increased OVCA-initiating cells and tumor formation in vivo through Bmi1. In contrast to its action in hemopoietic malignancies, DNA methyl transferase 3A (DNMT3A) appears to play a pro-oncogenic role in ovarian cancer. VEGFA-driven Src increased DNMT3A leading to miR-128-2 methylation and upregulation of Bmi1 to increase stem-like cells. SRC knockdown was rescued by antagomir to miR-128. DNMT3A knockdown prevented VEGFA-driven miR-128-2 loss, and the increase in Bmi1 and tumor spheres. Analysis of over 1,300 primary human OVCAs revealed an aggressive subset in which high VEGFA is associated with miR-128-2 loss. Thus, VEGFA stimulates OVCA stem-like cells through Src-DNMT3A-driven miR-128-2 methylation and Bmi1 upregulation.

Keywords: VEGFA; Bmi1; cancer stem‐like cell; epigenetic; miR‐128.

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Cell Line, Tumor
  • Cell Proliferation
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Isoenzymes / metabolism
  • MicroRNAs / metabolism*
  • Neoplastic Stem Cells / physiology*
  • Ovarian Neoplasms / pathology*
  • Polycomb Repressive Complex 1 / metabolism*
  • Retinal Dehydrogenase / metabolism
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • BMI1 protein, human
  • Isoenzymes
  • MIRN128 microRNA, human
  • MicroRNAs
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • Polycomb Repressive Complex 1