Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site

Molecular Cancer

Research

Carly J Broderick¹  Mustafa M Moazam²  Anton Bazarov³  Gail C Fraizer⁴  Kurtis Eisermann⁵ 

[1] Department of Biological Sciences, Kent State University, Kent, OH, USA;Department of Pediatric Hematology/Oncology, Akron Children’s Hospital, Akron, OH, USA;School of Biomedical Sciences, Kent State University, Kent, OH, USA;School of Biomedical Sciences, Kent State University, Kent, OH, USA;Department of Biological Sciences, Kent State University, Kent, OH, USA;School of Biomedical Sciences, Kent State University, Kent, OH, USA;Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA;

关键词: Vascular Endothelial Growth Factor;    Androgen Receptor;    Vascular Endothelial Growth Factor Expression;    LNCaP Cell;    Core Promoter;   

DOI  :  10.1186/1476-4598-12-7

 received in 2012-05-23, accepted in 2013-01-21,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundVascular 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.ResultsThree 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Eisermann et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.