The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer
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Yanan Zhang1,2, Jie Liu1, Jing Lin3, Lei Zhou4, Yuhua Song5, Bo Wei6, Xiaoli Luo1, Zhida Chen1,6, Yingjie Chen1,5, Jiaxiu Xiong1,6, Xiaojie Xu1, Lihua Ding1, Qinong Ye1,2
1Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People’s Republic of China
2Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People’s Republic of China
3First Affiliated Hospital, Chinese PLA General Hospital, Beijing, People’s Republic of China
4Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China
5The Affiliated Hospital of Qing Dao University, Qingdao, People’s Republic of China
6Department of General Surgery, Chinese PLA General Hospital, Beijing, People’s Republic of China
Qinong Ye, e-mail: firstname.lastname@example.org
Lihua Ding, e-mail: email@example.com
Keywords: VEGF, angiogenesis, tumor growth, GATA1, SET7
Received: October 13, 2015 Accepted: January 18, 2016 Published: February 02, 2016
Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis. However, how transcription factors interact with histone-modifying enzymes to regulate VEGF transcription and tumor angiogenesis remains unclear. Here, we show that transcription factor GATA1 associates with the histone methyltransferase SET7 to promote VEGF transcription and breast tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that GATA1 was required for recruitment of SET7, RNA polymerase II and transcription factor II B to VEGF core promoter. GATA1 enhanced breast cancer cell (MCF7, ZR75-1 and MDA-MB-231)-secreted VEGF via SET7, which promoted vascular endothelial cell (HUVEC) proliferation, migration and tube formation. SET7 was required for GATA1-induced breast tumor angiogenesis and growth in nude mice. Immunohistochemical staining showed that expression of GATA1 and SET7 was upregulated and positively correlated with VEGF expression and microvessel number in 80 breast cancer patients. GATA1 and SET7 are independent poor prognostic factors in breast cancer. Our data provide novel insights into VEGF transcriptional regulation and suggest GATA1/SET7 as cancer therapeutic targets.
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