Abstract
PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present study, we evaluated the effects of the expression of PDEF on total/phosphoprotein levels of YAP1 (a downstream effector of the Hippo pathway). We observed that the PC3 and DU145 cells transfected with PDEF (PDEF-PC3 and PDEF-DU145) showed an increased phospho-YAP1 (Ser127) and total YAP1 levels as compared to the respective PC3 vector control (VC-PC3) and DU145 vector control cells (VC-DU145). We also observed an increased cytoplasmic YAP1 levels in PDEF-PC3 cells as compared to VC-PC3 cells. Moreover, our gene set enrichment analysis (GSEA) of mRNA expression in PDEF-PC3 and VC-PC3 cells revealed that PDEF resulted in inhibition of YAP1 target genes, directly demonstrating that PDEF plays a critical role in modulating YAP1 activity, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 mRNA levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels, which we had reported earlier, and we observed a direct correlation between PDEF and YAP1 expression in CRPC data set. To the best of our knowledge, these results provide the first demonstration of inhibiting YAP1 activity by PDEF in any system and suggest a cross-talk between PDEF and the Hippo signaling pathway.
Highlights
Prostate cancer (PCa) is the second most common cause of cancer deaths in men in the USA
To further elucidate the mechanistic role of PDEF in regulating YAP1 levels, we analyzed mRNA expression data generated in the Affymetrix format, from PDEF-PC3 and VC-PC3 cells that we have described previously (GSE108641) [25]
Gene set enrichment analysis (GSEA) of mRNA expression in PDEF-PC3 and VC-PC3 cells revealed that PDEF inhibits expression of YAP1 target genes (Figure 1D), directly demonstrating that PDEF plays a critical role in modulating YAP1 transcriptional activity, and by extension in the regulation of the Hippo pathway
Summary
Prostate cancer (PCa) is the second most common cause of cancer deaths in men in the USA. YAP lacks a DNA-binding domain and interacts with other transcription factors, such as Transcriptional Enhanced Associate Domain (TEAD), to bind DNA and regulate gene expression [7] Multiple signaling events such as cell–cell contact, cell density/polarization, mechano-transduction, G-protein coupled receptor-mediated signaling regulate Hippo pathway activation [8]. Analysis of YAP1 and PDEF in the neuroendocrine prostate cancer (NEPC)/CRPC dataset showed a further decrease in YAP1 as well as PDEF mRNA levels in NEPC as compared to CRPC, and a direct correlation between PDEF and YAP1 expression These exciting results show for the first time the inhibition of YAP1 transcriptional activity by PDEF, and a potential cross-talk between PDEF and the Hippo pathway
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