The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners.

Yanan Zhang,Jie Zhu,Xiaoli Luo,Jing Lin,Lihua Ding,Jie Liu,Zhaohui Lv,Shibin Wang,Qinong Ye,Yang Li

doi:10.18632/oncotarget.8060

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.

Highlights

Angiogenesis plays a critical role in the development and progression of cancer since adequate blood supply is necessary for cancer cell growth, invasion and metastasis [1]
We found that DEK promoted Vascular endothelial growth factor (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 1a (HIF-1a), a master regulator of tumor angiogenesis and growth
Since hypoxia is a key phenomenon in cancers [6], we tested whether DEK has a role in regulation of VEGF promoter activity and expression under hypoxic conditions using luciferase reporter assay, real-time reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA)

Summary

Introduction

Angiogenesis plays a critical role in the development and progression of cancer since adequate blood supply is necessary for cancer cell growth, invasion and metastasis [1]. Vascular endothelial growth factor (VEGF) ( known as VEGF-A), a key regulator of angiogenesis, is a dimeric glycoprotein secreted by many types of cells, including cancer cells, peripheral blood mononuclear cells, and fibroblast cells, but usually not endothelial cells [2,3,4,5]. Hypoxia-inducible factor 1α (HIF-1α) is a master regulator responsible for www.impactjournals.com/oncotarget the induction of genes that assist cancer cells to survive and metastasize from normoxia to hypoxia [7, 8]. The heterodimeric complex binds to hypoxia response element (HRE) upstream of hypoxia-regulated genes, modulating expression of a variety of HIF-1 target genes, including VEGF. Increased tumor HIF-1α is correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1α as a cancer drug target [9, 10]. Chemotherapeutic drugs targeting VEGF and HIF-1α have limited efficacy against cancer and even cause adverse effects, suggesting that the mechanisms of VEGF- and HIF-1α-related function need to be further elucidated

Methods

Results

Conclusion