Uncovering Androgen Responsive Regulatory Networks in Prostate Cancer

Eisermann, Kurtis; Bazarov, Anton; Brett, Adina; Knapp, Ethan; Piontkivska, Helen; Fraizer, Gail

doi:10.1109/occbio.2009.21

Cited by 4 publications

(11 citation statements)

References 25 publications

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“…As expected, nonclassical AR half-sites were identified adjacent to WT1/EGR1/Sp1 sites in 8 of 11 promoters analyzed including VEGF (114). Binding at one of the three predicted nonclassical androgen receptor element half-sites (ARE-I) in the VEGF promoter region was tested by ChIP analysis of hormone-treated, WT1-transfected LNCaP cells (114). Endogenous AR and Sp1 proteins, along with exogenous WT1, were immunoprecipitated from native chromatin of these hormone-treated cells, indicating that the predicted WT1, Sp1, and AR sites in the VEGF proximal promoter region were functional and suggesting that the three factors may bind individually or as a complex.…”

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hsupporting

confidence: 78%

“…Thus, we asked whether AR might bind at other sites via interaction with other zinc finger transcription factors (ZFTFs), such as SP1, EGR-1, or WT1. We hypothesized that if AR-ZFTF interactions were important mediators of androgen response, then cognate-binding sites should be located within the promoter regions of hormone-responsive genes expressed in PC (101,114). As expected, nonclassical AR half-sites were identified adjacent to WT1/EGR1/Sp1 sites in 8 of 11 promoters analyzed including VEGF (114).…”

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hmentioning

confidence: 79%

“…We hypothesized that if AR-ZFTF interactions were important mediators of androgen response, then cognate-binding sites should be located within the promoter regions of hormone-responsive genes expressed in PC (101,114). As expected, nonclassical AR half-sites were identified adjacent to WT1/EGR1/Sp1 sites in 8 of 11 promoters analyzed including VEGF (114). Binding at one of the three predicted nonclassical androgen receptor element half-sites (ARE-I) in the VEGF promoter region was tested by ChIP analysis of hormone-treated, WT1-transfected LNCaP cells (114).…”

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hmentioning

confidence: 99%

“…Because estrogen regulation of the VEGF core promoter has been shown to require Sp1 sites in breast cancer cells (109), we asked whether androgen might regulate VEGF in a similar fashion in PC cells. Sp1-associated binding of AR to novel-binding sites in the VEGF promoter was demonstrated in vivo by ChIP analysis in LNCaP cells (101,104,114). AR and Sp1 formed a nuclear complex and were shown to bind to the VEGF core promoter in hormone-treated CWR22Rv1 PC cells (104).…”

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hmentioning

confidence: 99%

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Functional Role of WT1 in Prostate Cancer

et al. 2016

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Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. AbstractAlthough initial discoveries of Wilms tumor 1 (WT1) expression in extrarenal disease generated controversy, we and others have examined WT1 expression in non-Wilms cancers and have demonstrated that the WT1(A) isoform, lacking the lysine-threonine-serine tripeptide (KTS) insertion, transcriptionally regulates the expression of growth control genes in other cancer types. Here, we review our evidence that WT1 is expressed in prostate cancer (PC) epithelial cells and regulates PC critical genes. That WT1 may promote metastatic disease is consistent with previous findings that WT1 suppressed E-cadherin and enhanced motility of PC cells with low migratory and metastatic potential. Recent findings led us to askFraizer et al. 236whether WT1 acts as an angiogenic switch in PC. Although vascular endothelial growth factor (VEGF) is regulated at several levels and by a number of different factors, a mechanistic understanding of WT1-mediated transcriptional regulation in PC cells was previously lacking. Here, we discuss the evidence of WT1-and androgen receptor (AR)-binding sites in the VEGF promoter and show the potential for cooperation between hormone and WT1. These findings revealed that in AR-intact PC cells, WT1 was sufficient to upregulate VEGF transcription, and WT1 expression enhanced the hormone activation of VEGF expression. This notion that WT1 can activate an angiogenic switch in PC cells, to enhance tumor growth and progression to metastatic disease, is consistent with our understanding of the oncogenic nature of WT1 overexpression in inappropriate tissues or at inappropriate times. The potential for WT1 to promote both tumor angiogenesis and PC cell migration suggests that WT1 regulates genes that promote PC progression to lethal metastatic disease. Therapies targeting WT1 in PC may reduce metastatic spread and increase overall survival.

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Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hsupporting

confidence: 78%

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hmentioning

confidence: 79%

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hmentioning

confidence: 99%

Section: Combined Androgen and Wt1 Activation Of Vegf Expression In Hmentioning

confidence: 99%

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Functional Role of WT1 in Prostate Cancer

et al. 2016

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“…Non-classical AR half-sites were also identified adjacent to G-rich WT1/EGR1/Sp1 sites in 8 of 11 promoters analyzed, including VEGF [50]. Co-transfection of WT1 expression plasmids enhances VEGF promoter activity [18,24], with addition of the androgen analog R1881 increasing WT1 effectiveness, and mutation of a WT1 site reducing VEGF promoter activity [18].…”

Section: Transcription Factors That Regulate Androgen Induction Ofmentioning

confidence: 99%

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

Eisermann

Fraizer

2017

Cancers

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Prostate cancer progression is controlled by the androgen receptor and new blood vessel formation, or angiogenesis, which promotes metastatic prostate cancer growth. Angiogenesis is induced by elevated expression of vascular endothelial growth factor (VEGF). VEGF is regulated by many factors in the tumor microenvironment including lowered oxygen levels and elevated androgens. Here we review evidence delineating hormone mediated mechanisms of VEGF regulation, including novel interactions between the androgen receptor (AR), epigenetic and zinc-finger transcription factors, AR variants and the hypoxia factor, HIF-1. The relevance of describing the impact of both hormones and hypoxia on VEGF expression and angiogenesis is revealed in recent reports of clinical therapies targeting both VEGF and AR signaling pathways. A better understanding of the complexities of VEGF expression could lead to improved targeting and increased survival time for a subset of patients with metastatic castration-resistant prostate cancer.

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Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection

et al. 2010

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BackgroundThe prostate gland represents a multifaceted system in which prostate epithelia and stroma have distinct physiological roles. To understand the interaction between stroma and glandular epithelia, it is essential to delineate the gene expression profiles of these two tissue types in prostate cancer. Most studies have compared tumor and normal samples by performing global expression analysis using a mixture of cell populations. This report presents the first study of prostate tumor tissue that examines patterns of differential expression between specific cell types using laser capture microdissection (LCM).MethodsLCM was used to isolate distinct cell-type populations and identify their gene expression differences using oligonucleotide microarrays. Ten differentially expressed genes were then analyzed in paired tumor and non-neoplastic prostate tissues by quantitative real-time PCR. Expression patterns of the transcription factors, WT1 and EGR1, were further compared in established prostate cell lines. WT1 protein expression was also examined in prostate tissue microarrays using immunohistochemistry.ResultsThe two-step method of laser capture and microarray analysis identified nearly 500 genes whose expression levels were significantly different in prostate epithelial versus stromal tissues. Several genes expressed in epithelial cells (WT1, GATA2, and FGFR-3) were more highly expressed in neoplastic than in non-neoplastic tissues; conversely several genes expressed in stromal cells (CCL5, CXCL13, IGF-1, FGF-2, and IGFBP3) were more highly expressed in non-neoplastic than in neoplastic tissues. Notably, EGR1 was also differentially expressed between epithelial and stromal tissues. Expression of WT1 and EGR1 in cell lines was consistent with these patterns of differential expression. Importantly, WT1 protein expression was demonstrated in tumor tissues and was absent in normal and benign tissues.ConclusionsThe prostate represents a complex mix of cell types and there is a need to analyze distinct cell populations to better understand their potential interactions. In the present study, LCM and microarray analysis were used to identify novel gene expression patterns in prostate cell populations, including identification of WT1 expression in epithelial cells. The relevance of WT1 expression in prostate cancer was confirmed by analysis of tumor tissue and cell lines, suggesting a potential role for WT1 in prostate tumorigenesis.

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Uncovering Androgen Responsive Regulatory Networks in Prostate Cancer

Cited by 4 publications

References 25 publications

Functional Role of WT1 in Prostate Cancer

Functional Role of WT1 in Prostate Cancer

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

Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection

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