title: The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners.
abstract: 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.
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People's Republic of China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: First Affiliated Hospital, Chinese PLA General Hospital, Beijing, People's Republic of China.
authors.forename: Shibin
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Luo
authors.affiliation: First Affiliated Hospital, Chinese PLA General Hospital, Beijing, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, People's Republic of China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: First Affiliated Hospital, Chinese PLA General Hospital, Beijing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People's Republic of China.
authors.forename: Qinong
authors.initials: Q
authors.lastname: Ye
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: DEK; HIF-1α; VEGF; angiogenesis; tumor growth