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

Metastasis is the primary cause of prostate cancer (PCa) morbidity and mortality. Our previous studies revealed that Sam pointed domain ETS transcription factor a.k.a. prostate-derived ETS factor (SPDEF/PDEF), inhibits PCa metastasis. However, the mechanism is still unclear.  In this study, using micro-array and gene set enrichment analysis, we discovered that PDEF upregulated epithelial/luminal differentiation related genes while suppressed stemness and EMT related genes especially Twist1. We also observed loss of PDEF and gain of Twist1 expression during PCa 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 PCa 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 PCa 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 PCa.   Implications: This study reports the novel findings that PDEF surpasses Twist 1 and that PDEF/Twist1 could help distinguish between lethal and indolent PCa.