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 language | English (US) |
|---|---|
| Pages (from-to) | 304-318 |
| Number of pages | 15 |
| Journal | EMBO Molecular Medicine |
| Volume | 9 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2017 |
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Keywords
- Bmi1
- cancer stem-like cell
- epigenetic
- miR-128
- VEGFA
ASJC Scopus subject areas
- Molecular Medicine
Cite this
VEGFA activates an epigenetic pathway upregulating ovarian cancer-initiating cells. / Jang, Kibeom; Kim, Minsoon; Gilbert, Candace A.; Simpkins, Fiona; Ince, Tan; Slingerland, Joyce M.
In: EMBO Molecular Medicine, Vol. 9, No. 3, 01.03.2017, p. 304-318.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - VEGFA activates an epigenetic pathway upregulating ovarian cancer-initiating cells
AU - Jang, Kibeom
AU - Kim, Minsoon
AU - Gilbert, Candace A.
AU - Simpkins, Fiona
AU - Ince, Tan
AU - Slingerland, Joyce M
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - Bmi1
KW - cancer stem-like cell
KW - epigenetic
KW - miR-128
KW - VEGFA
UR - http://www.scopus.com/inward/record.url?scp=85012273643&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85012273643&partnerID=8YFLogxK
U2 - 10.15252/emmm.201606840
DO - 10.15252/emmm.201606840
M3 - Article
C2 - 28179359
AN - SCOPUS:85012273643
VL - 9
SP - 304
EP - 318
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 3
ER -