The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners
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Yanan Zhang1,2,*, Jie Liu1,*, Shibin Wang3,*, Xiaoli Luo1,*, Yang Li3, Zhaohui Lv4, Jie Zhu4, Jing Lin3, 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
4Department of Endocrinology, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, People’s Republic of China
*These authors have contributed equally to this work
Qinong Ye, email: email@example.com
Lihua Ding, email: firstname.lastname@example.org
Jing Lin, email: email@example.com
Keywords: angiogenesis, VEGF, DEK, HIF-1α, tumor growth
Received: October 08, 2015 Accepted: February 29, 2016 Published: March 14, 2016
The DEK oncogene is overexpressed in various cancers and overexpression of DEK correlates with poor clinical outcome. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis, a process essential for tumor growth and metastasis. However, whether DEK enhances tumor angiogenesis remains unclear. Here, we show that DEK is a key regulator of VEGF expression and tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that DEK promoted VEGF transcription in breast cancer cells (MCF7, ZR75-1 and MDA-MB-231) by directly binding to putative DEK-responsive element (DRE) of the VEGF promoter and indirectly binding to hypoxia response element (HRE) upstream of the DRE through its interaction with the transcription factor hypoxia-inducible factor 1α (HIF-1α), a master regulator of tumor angiogenesis and growth. DEK is responsible for recruitment of HIF-1α and the histone acetyltransferase p300 to the VEGF promoter. DEK-enhanced VEGF increases vascular endothelial cell proliferation, migration and tube formation as well as angiogenesis in the chick chorioallantoic membrane. DEK promotes tumor angiogenesis and growth in nude mice in HIF-1α-dependent and -independent manners. Immunohistochemical staining showed that DEK expression positively correlates with the expression of VEGF and microvessel number in 58 breast cancer patients. Our data establish DEK as a sequence-specific binding transcription factor, a novel coactivator for HIF-1α in regulation of VEGF transcription and a novel promoter of angiogenesis.
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