Mechanisms and Functional Consequences of PDEF Protein Expression Loss During Prostate Cancer Progression

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
The Prostate (Impact Factor: 3.57). 12/2011; 71(16):1723-35. DOI: 10.1002/pros.21389
Source: PubMed


Ets is a large family of transcriptional regulators with functions in most biological processes. While the Ets family gene, prostate-derived epithelial factor (PDEF), is expressed in epithelial tissues, PDEF protein expression has been found to be reduced or lost during cancer progression. The goal of this study was to examine the mechanism for and biologic impact of altered PDEF expression in prostate cancer.
PDEF protein expression of prostate specimens was examined by immunohistochemistry. RNA and protein expression in cell lines were measured by q-PCR and Western blot, respectively. Cellular growth was determined by quantifying viable and apoptotic cells over time. Cell cycle was measured by flow cytometry. Migration and invasion were determined by transwell assays. PDEF promoter occupancy was determined by chromatin immunoprecipitation (ChIP).
While normal prostate epithelium expresses PDEF mRNA and protein, tumors show no or decreased PDEF protein expression. Re-expression of PDEF in prostate cancer cells inhibits cell growth. PDEF expression is inversely correlated with survivin, urokinase plasminogen activator (uPA) and slug expression and ChIP studies identify survivin and uPA as direct transcriptional targets of PDEF. This study also shows that PDEF expression is regulated via a functional microRNA-204 (miR-204) binding site within the 3'UTR. Furthermore, we demonstrate the biologic significance of miR-204 expression and that miR-204 is over-expressed in human prostate cancer specimens.
Collectively, the reported studies demonstrate that PDEF is a negative regulator of tumor progression and that the miR-204-PDEF regulatory axis contributes to PDEF protein loss and resultant cancer progression.

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Available from: Dennis K Watson, Oct 09, 2015
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    • "One of the first studies providing evidences for the involvement of a specific miRNA in the etiology of human PAH focused on the downregulation of miR-204 (Table 1),[141] which had been previously shown to be associated with cell proliferation in cancer cells[142] and epithelial retinal depolarization.[143] In PASMC STAT3 mediates downregulation of miR-204 which enhances the activity of Src thereby increasing proliferation and resistance to apoptosis.[141] "
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    • "In vitro DNA-binding studies support this model, as the ETS proteins ETV1, ERG, and FLI1, but not ETS2 and SPI1, are reported to bind DNA cooperatively with AP-1 (Verger et al. 2001; Kim et al. 2006). SPDEF and EHF are candidates for occupancy in normal prostate because they are the two most highly expressed ETS family members in this tissue (Hollenhorst et al. 2004) and knockdown of these factors increases survival and migration of prostate cancer cell lines (Gu et al. 2007; Cangemi et al. 2008; Turner et al. 2011). However, our ability to overexpress SPDEF and further decrease PLAU expression (Fig. 4C) indicates that we can drive increased occupancy in RWPE-1 cells. "
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    ABSTRACT: The prostate-derived ETS factor (PDEF) is the latest family member of the ETS transcription factor family, although it is unique in many aspects. PDEF was first described as an mRNA transcript highly expressed in prostate tumor cells where it regulates prostate-specific antigen gene expression and is an androgen receptor co-regulator. PDEF expression is highly restricted to epithelial cells and has only been found in prostate, breast, colon, ovary, gastric, and airway epithelium. Strong preclinical evidence is emerging that PDEF is a negative regulator of tumor progression and metastasis. PDEF expression is often lost in late-stage, advanced tumors. The induction of tumor aggressiveness in response to the loss of PDEF is thought to be due to the plethora of PDEF-regulated gene targets, many of which are known players in tumor progression including tumor cell invasion and metastasis. These data have lead to the hypothesis that PDEF may function as a tumor metastasis suppressor. In this review, we summarize what is known about PDEF since its discovery over a decade ago and give a detailed overview of PDEF-regulated gene products and the expression profiles of PDEF in clinical tumor samples.
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