VEGFA activates an epigenetic pathway upregulating ovarian cancer-initiating cells

Kibeom Jang, Minsoon Kim, Candace A. Gilbert, Fiona Simpkins, Tan A. Ince, Joyce M. Slingerland

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)304-318
Number of pages15
JournalEMBO Molecular Medicine
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2017

Keywords

  • Bmi1
  • cancer stem-like cell
  • epigenetic
  • miR-128
  • VEGFA

ASJC Scopus subject areas

  • Molecular Medicine

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