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首页> 外文期刊>Molecular Cancer >Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site
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Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site

机译：雄激素通过Sp1结合位点上调前列腺癌细胞中血管内皮生长因子的表达

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Background Vascular Endothelial Growth Factor (VEGF) is regulated by a number of different factors, but the mechanism(s) behind androgen-mediated regulation of VEGF in prostate cancer are poorly understood. Results Three novel androgen receptor (AR) binding sites were discovered in the VEGF promoter and in vivo binding of AR to these sites was demonstrated by chromatin immunoprecipitation. Mutation of these sites attenuated activation of the VEGF promoter by the androgen analog, R1881 in prostate cancer cells. The transcription factors AR and Sp1 were shown to form a nuclear complex and both bound the VEGF core promoter in chromatin of hormone treated CWR22Rv1 prostate cancer cells. The importance of the Sp1 binding site in hormone mediated activation of VEGF expression was demonstrated by site directed mutagenesis. Mutation of a critical Sp1 binding site (Sp1.4) in the VEGF core promoter region prevented activation by androgen. Similarly, suppression of Sp1 binding by Mithramycin A treatment significantly reduced VEGF expression. Conclusions Our mechanistic study of androgen mediated induction of VEGF expression in prostate cancer cells revealed for the first time that this induction is mediated through the core promoter region and is dependent upon a critical Sp1 binding site. The importance of Sp1 binding suggests that therapy targeting the AR-Sp1 complex may dampen VEGF induced angiogenesis and, thereby, block prostate cancer progression, helping to maintain the indolent form of prostate cancer.
机译：背景技术血管内皮生长因子（VEGF）受许多不同因素的调节，但是对雄激素介导的前列腺癌VEGF调节的机制了解甚少。结果在VEGF启动子中发现了三个新的雄激素受体（AR）结合位点，并且通过染色质免疫沉淀证明了AR与这些位点的体内结合。这些位点的突变减弱了前列腺癌细胞中雄激素类似物R1881对VEGF启动子的激活。显示转录因子AR和Sp1形成核复合物，并且都结合激素治疗的CWR22Rv1前列腺癌细胞的染色质中的VEGF核心启动子。通过位点定向诱变证明了Sp1结合位点在激素介导的VEGF表达激活中的重要性。 VEGF核心启动子区域中关键Sp1结合位点（Sp1.4）的突变阻止了雄激素的激活。同样，用光神霉素A抑制Sp1结合会显着降低VEGF的表达。结论我们对雄激素介导的前列腺癌细胞中VEGF表达诱导的机理研究首次揭示了这种诱导是通过核心启动子区域介导的，并且依赖于关键的Sp1结合位点。 Sp1结合的重要性表明，靶向AR-Sp1复合物的疗法可能会抑制VEGF诱导的血管生成，从而阻断前列腺癌的进展，从而有助于维持惰性形式的前列腺癌。

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