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 orSRCknockdown. VEGFA stimulated sphere formation only in the ALDH1+subpopulation and increased OVCA-initiating cells and tumor formationin vivothrough 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 tomiR-128-2methylation and upregulation of Bmi1 to increase stem-like cells.SRCknockdown was rescued by antagomir to miR-128.DNMT3Aknockdown prevented VEGFA-drivenmiR-128-2loss, 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 withmiR-128-2loss. Thus, VEGFA stimulates OVCA stem-like cells through Src-DNMT3A-drivenmiR-128-2methylation and Bmi1 upregulation.
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Kibeom
K
Jang
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Minsoon
M
Kim
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Candace A
CA
Gilbert
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Obstetrics & Gynecology, University of Miami Miller School of Medicine, Miami, FL, USA.
Fiona
F
Simpkins
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA.|Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
Tan A
0000-0003-0315-6425
TA
Ince
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA jslingerland@med.miami.edu.|Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
Joyce M
0000-0003-1487-8554
JM
Slingerland
D000080924:Aldehyde Dehydrogenase 1 Family; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D050697:Retinal Dehydrogenase / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C069077:BMI1 protein, human; D007527:Isoenzymes; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D063150:Polycomb Repressive Complex 1

VEGFA
; Bmi1; cancer stem‐like cell; epigenetic; miR‐128