Evolutionary conservation of zinc finger transcription factor binding sites in promoters of genes co-expressed with WT1 in prostate cancer

Eisermann, Kurtis; Tandon, Sunpreet; Bazarov, Anton; Brett, Adina; Fraizer, Gail; Piontkivska, Helen

doi:10.1186/1471-2164-9-337

Cited by 23 publications

(29 citation statements)

References 98 publications

(91 reference statements)

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“…The relevance of WT1 to PC has been shown by finding that WT1 mRNA and protein are more often expressed in high-grade, invasive PC than lowgrade localized tumors and that WT1 is not expressed in BPH or non-neoplastic prostate tissue (49). The identification of potential WT1-binding sites in the regulatory sequences of cancer-critical genes expressed in PC epithelial cells, together with the demonstration of WT1 protein bound to these gene promoters in native chromatin of transfected LNCaP cells, supported the notion that elevated WT1 expression in prostate epithelial cells affects transcriptional modulation of homeostatic genes important for PC (101). That WT1 may promote metastatic disease is consistent with previous findings that WT1 suppressed E-cadherin, thereby increasing motility and metastatic potential of PC cells (48).…”

Section: Resultssupporting

confidence: 49%

“…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: 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%

“…WT1-binding sites predicted by in silico analysis of the VEGF proximal promoter (101,102) were demonstrated functional by reporter assays and protein binding in vitro and in vivo using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays, respectively. The latter result indicated the ability of WT1 protein to bind to native chromatin in LNCaP PC cells was used to determine if this site was necessary for WT1-mediated transcriptional activation of the VEGF promoter.…”

Section: Regulation Of Vegf By Wt1 In Prostate Cancermentioning

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: Resultssupporting

confidence: 49%

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%

Section: Regulation Of Vegf By Wt1 In Prostate Cancermentioning

confidence: 99%

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Functional Role of WT1 in Prostate Cancer

et al. 2016

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“…Given the growing body of evidence that VEGF-A is a WT1 target, [11][12][13] we hypothesized that Wt1 may be regulating Vegf-a in EBs and tested whether exogenous Vegf-a protein could restore hematopoiesis in Wt1-null EBs. Exogenous Vegf-a restored close to normal hematopoietic colony-forming potential to Wt1-deficient cells (Figure 2A) by reducing apoptosis of Ter119 1ve progenitors lacking Wt1 (Figure 2B-C).…”

Section: Vementioning

confidence: 99%

WT1 regulates murine hematopoiesis via maintenance of VEGF isoform ratio

Cunningham

Palumbo

Grosso

et al. 2013

Blood

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Mutations in theWilms tumor suppressor 1 (WT1) gene are as frequent in acutemyeloid leukemia (AML) as in nephroblastma and predict poor prognosis. However, the role of WT1 in hematopoiesis remains unclear. We show that Wt1-deficient mouse embryonic stem cells exhibit reduced hematopoietic potential caused by vascular endothelial growth factor A (Vegf-a)–dependent apoptosis of hematopoietic progenitor cells associated with overproduction of the Vegf-a120 isoform. We demonstrate that Wt1 promotes exon inclusion using a Vegf-a minigene-based splicing assay. These data identify a critical role for Wt1 in hematopoiesis and Vegf-a as a cellular RNA whose splicing is potentially regulated by Wt1. The correction of Wt1 deficiency by treatment with exogenous Vegf-a protein indicates that the Wt1/Vegf-a axis is a molecular pathway that could be exploited for the management/treatment of poor prognosis AMLs

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Identifying potential anti‐metastasis drugs for prostate cancer through integrative bioinformatics analysis and compound library screening

Hong

Peng

et al. 2023

The Journal of Gene Medicine

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BackgroundMetastasis poses the greatest threat to the lives of individuals with prostate cancer. Therefore, it is imperative to identify the underlying mechanism driving metastasis. Doing so would facilitate the detection of new diagnostic biomarkers and the advancement of treatment options for patients.MethodsMetastasis‐related modules were identified through weighted gene co‐expression network analysis based on microarray GSE6919. Hub genes were confirmed by quantitative real‐time PCR across different prostate cell lines and clinic samples. Pivotal genes were determined through integration of RNA and transcription factor‐target associated interactions. To predict drugs with potential to suppress tumor metastasis, we applied molecular networks using the DrugBank database. Drug repositioning analysis and confirmation of drug screen were conducted using the compound library. Confirmation of selective cytotoxicity of cupric oxide was carried out via invasion, transwell and apoptosis assays.ResultsWe identified five metastasis‐related modules. Of these modules, two were identified to represent core dysfunction modules in which five hub genes were determined for each module. Five of these 10 genes correlating with prostate cancer progression. Furthermore, our analysis revealed that there are 36 drugs with the potential to be active against tumor metastasis. Finally, we identified four compounds that have not previously been reported to have any association with cancer therapy. Of these, cupric oxide was determined to have the best chemotherapeutic potential in treating prostate cancer metastasis.ConclusionsBy combining bioinformatics methods with compound library screening, this study proposes a valuable approach to drug discovery. Cupric oxide showed the potential in the treatment of prostate cancer metastasis and deserves further study.

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Evolutionary conservation of zinc finger transcription factor binding sites in promoters of genes co-expressed with WT1 in prostate cancer

Cited by 23 publications

References 98 publications

Functional Role of WT1 in Prostate Cancer

Functional Role of WT1 in Prostate Cancer

WT1 regulates murine hematopoiesis via maintenance of VEGF isoform ratio

Identifying potential anti‐metastasis drugs for prostate cancer through integrative bioinformatics analysis and compound library screening

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