VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells
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 VEG...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606840 |
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| author | Kibeom Jang Minsoon Kim Candace A Gilbert Fiona Simpkins Tan A Ince Joyce M Slingerland |
| author_facet | Kibeom Jang Minsoon Kim Candace A Gilbert Fiona Simpkins Tan A Ince Joyce M Slingerland |
| author_sort | Kibeom Jang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0f1b4fb2289b48ca8f2cf0f945f01ce9 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-02-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-0f1b4fb2289b48ca8f2cf0f945f01ce92025-08-20T03:43:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-02-019330431810.15252/emmm.201606840VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cellsKibeom Jang0Minsoon Kim1Candace A Gilbert2Fiona Simpkins3Tan A Ince4Joyce M Slingerland5Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineBraman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineBraman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineBraman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineBraman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineBraman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineAbstract 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.https://doi.org/10.15252/emmm.201606840Bmi1epigeneticmiR‐128ovarian cancer stem cellVEGFVEGFA |
| spellingShingle | Kibeom Jang Minsoon Kim Candace A Gilbert Fiona Simpkins Tan A Ince Joyce M Slingerland VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells EMBO Molecular Medicine Bmi1 epigenetic miR‐128 ovarian cancer stem cell VEGF VEGFA |
| title | VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells |
| title_full | VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells |
| title_fullStr | VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells |
| title_full_unstemmed | VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells |
| title_short | VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells |
| title_sort | vegfa activates an epigenetic pathway upregulating ovarian cancer initiating cells |
| topic | Bmi1 epigenetic miR‐128 ovarian cancer stem cell VEGF VEGFA |
| url | https://doi.org/10.15252/emmm.201606840 |
| work_keys_str_mv | AT kibeomjang vegfaactivatesanepigeneticpathwayupregulatingovariancancerinitiatingcells AT minsoonkim vegfaactivatesanepigeneticpathwayupregulatingovariancancerinitiatingcells AT candaceagilbert vegfaactivatesanepigeneticpathwayupregulatingovariancancerinitiatingcells AT fionasimpkins vegfaactivatesanepigeneticpathwayupregulatingovariancancerinitiatingcells AT tanaince vegfaactivatesanepigeneticpathwayupregulatingovariancancerinitiatingcells AT joycemslingerland vegfaactivatesanepigeneticpathwayupregulatingovariancancerinitiatingcells |