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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    • "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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