Prostate-Derived Ets Factor (PDEF) Inhibits Metastasis by Inducing Epithelial/Luminal Phenotype in Prostate Cancer Cells

Abstract

Metastasis is the primary cause of prostate cancer morbidity and mortality. Our previous studies revealed that Sam pointed domain ETS transcription factor, a.k.a. prostate-derived ETS factor (SPDEF/PDEF), inhibits prostate cancer metastasis. However, the mechanism is still unclear. In this study, using microarray and gene set enrichment analysis, we discovered that PDEF upregulated epithelial/luminal differentiation-related genes while it suppressed stemness and epithelial-to-mesenchymal transition-related genes, especially Twist1. We also observed loss of PDEF and gain of Twist1 expression during prostate cancer progression in the TRAMP mouse model. Moreover, Twist1 knockdown resulted in upregulation of PDEF expression, suggesting a reciprocal regulation between PDEF and Twist1. Mechanistically, our ChIP-seq analysis revealed that PDEF directly regulated cytokeratin 18 (CK18) transcription through the GGAT motif within its putative promoter region. CK18 knockdown resulted in increased expression of Twist1, suggesting that PDEF regulated Twist1 in part via CK18. Our analysis of multiple clinical prostate cancer cohorts revealed an inverse relationship between PDEF expression and tumor grade, tumor metastasis, and poor patient survival. Furthermore, a two-gene signature of low PDEF and high Twist1 can better predict poor survival in prostate cancer patients than either gene alone. Collectively, our findings demonstrate PDEF inhibits prostate tumor progression, in part, by directly regulating transcription of CK18, and that PDEF/Twist1 expression could help distinguish between lethal and indolent prostate cancer. This study reports the novel findings that PDEF suppresses Twist1 partly via CK18 and that PDEF/Twist1 could help distinguish between lethal and indolent prostate cancer. http://mcr.aacrjournals.org/content/molcanres/16/9/1430/F1.large.jpg .

Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1): a target for cancer therapeutic intervention?

“…Trans-well cell invasion assay was performed in the presence and absence of 4EGI-1, a small molecule inhibitor of EIF4G-EIF4E complex and the results were analyzed as described previously [31].…”

Prostate-Derived ETS Factor (PDEF) Regulates Yes Associated Protein 1 (YAP1) in Prostate Cancer Cells: A Potential Cross-Talk between PDEF and Hippo Signaling

“…We observed PDEF-PC3 cells have a higher amount of YAP1 protein (total and phosphoprotein levels) compared to VC-PC3 cells (Figure 1 A). Analysis by immunofluorescence (IMF) 24 images for YAP1 showed more cytoplasmic/nuclear ratio of YAP1 in PDEF-PC3 cells as compared to VC-PC3 cells (Figure 1 B). These results are the first direct demonstration of regulation of YAP1 by PDEF in any system.…”

“…ETS transcription factors have been associated with tumor progression as well as therapy resistance in several cancers including prostate cancer. However, the role of PDEF in Prostate cancer remains debated [18][19][20][21][22][23][24][25] . Others and we 35,36 .…”

“…Altered expression of YAP1 has been associated with many solid tumors including PCa [9][10][11][12][13][14][15][16][17] . The role of PDEF in PCa remains highly debated [18][19][20][21][22][23][24][25] . We observed that PDEF suppresses EMT transition and metastasis in part by driving the expression of epithelial/luminal differentiationrelated genes 20,24 .…”

“…The role of PDEF in PCa remains highly debated [18][19][20][21][22][23][24][25] . We observed that PDEF suppresses EMT transition and metastasis in part by driving the expression of epithelial/luminal differentiationrelated genes 20,24 . Present studies investigated the relationship between PDEF expression and the Hippo pathway in PCa.…”