The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners.
The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners.
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DEK癌基因激活VEGF表达并以HIF-1a依赖性和非依赖性方式促进肿瘤血管生成和生长
DOI：
10.18632/oncotarget.8060
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Ye Q
中科院分区：
文献类型：
--
作者：
Zhang Y;Liu J;Wang S;Luo X;Li Y;Lv Z;Zhu J;Lin J;Ding L;Ye Q
DEK癌基因在多种癌症中均有过度表达，且其过度表达与临床预后不良有关。血管内皮生长因子(VEGF)是肿瘤血管生成的最重要调节因子，是肿瘤生长和转移所必需的过程。然而，DEK是否能促进肿瘤血管生成仍不清楚。在这里，我们表明DEK是血管内皮生长因子表达和肿瘤血管生成的关键调节因子。通过染色质免疫沉淀实验，我们发现DEK通过直接与血管内皮生长因子启动子的DEK反应元件(DRE)结合，并通过与肿瘤血管生成和生长的主要调节因子低氧诱导因子1α(HIF-1α)相互作用，间接与DRE上游的缺氧反应元件(HRE)结合，从而促进乳腺癌细胞(MCF7、ZR751和MDB231)中血管内皮生长因子的转录。DEK负责将低氧诱导因子-1α和组蛋白乙酰转移酶p300募集到血管内皮生长因子启动子。DEK增强的血管内皮生长因子促进鸡绒毛膜尿囊膜血管内皮细胞的增殖、迁移和管状形成以及血管生成。DEK通过HIF-1α依赖和非依赖方式促进裸鼠肿瘤血管生成和生长。免疫组织化学染色显示，58例乳腺癌组织中DEK的表达与VEGF的表达及微血管数呈正相关。我们的研究结果表明，DEK是一种序列特异性结合转录因子，是一种新的缺氧诱导因子-1α转录调控辅活化子，也是一种新的血管生成启动子。
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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影响因子：
5.6
作者：
Kristensen TB;Knutsson ML;Wehland M;Laursen BE;Grimm D;Warnke E;Magnusson NE
通讯作者：
Magnusson NE
影响因子：
15.8
作者：
Lee TH;Seng S;Sekine M;Hinton C;Fu Y;Avraham HK;Avraham S
通讯作者：
Avraham S
DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
DOI：
10.1073/pnas.0909353106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Lee, KangAe;Zhang, Huafeng;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
3.9
作者：
Liang, Yayun;Brekken, Rolf A.;Hyder, Salman M.
通讯作者：
Hyder, Salman M.