VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells

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.