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

Abstract

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.

The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer

“…Rather a single GC-box in the core promoter is essential for hormone responsiveness of the VEGF promoter [16]. This indicates that the AR is not bound to an ARE binding site, but rather is tethered via a ZFTF, which is bound to the GC boxes (Sp1/Sp3 binding sites) (Figure 1B).…”

Role of STAT3 pathway in genitourinary tumors

“…Indeed, STAT3 is required for VEGF signaling [57]. The relationship between STAT3 and AR in PCa is crucial in modulating VEGF transcription, may be due to the presence of AR-binding sites in the promoter of VEGF gene [58]. Moreover, STAT3-induced HIF1α transcription, which cooperates with STAT3 to induce VEGF expression [59].…”

Muscle weakness during aging: a deficiency state involving declining angiogenesis

“…The prostates of adult rats injected with dehydrotestosterone (DHT) showed a "a four-fold increase in VEGF specific activity" (Sordello et al, 1998). Numerous papers have reported that androgens up-regulate VEGF in cultures of normal and malignant human prostatic cells (Joseph et al, 1997;Sordello et al, 1998;Eisermann et al, 2013).…”