Abstract
Abstract Conventional therapies produce a high rate of cure for patients with localized prostate cancer (PCa), but there is no effective treatment for castration resistant metastatic PCa. Transcription factors by association with enhancer and super-enhancer elements are key drivers of cell identity. Our previous studies have shown that Sam Pointed Domain Ets Transcription Factor a.k.a. Prostate Derived Ets Factor (SPDEF/PDEF), inhibits cell migration, invasion and clonogenic activity in PCa cells and there is a graded loss of PDEF with increasing Gleason Score in PCa patient samples. PDEF has been reported to be one of the cell identity transcription factors in LNCaP cells. We proposed that PDEF functions as a putative tumor metastasis suppressor. Others have shown an increase in Twist1, a bHLH transcription factor, was positively correlated with Gleason Grading. Present study was designed to investigate the role of PDEF and interplay between PDEF and Twist1 in PCa. PC3 cells were stably transfected with PDEF/control PABABE vectors. Gene expression changes were monitored by Affymetrix microarray. Microarray was analyzed with GSEA. qRT-PCR was performed to confirm gene expression and IHC, IF and IB analysis were performed to visualize protein expression. Chip-seq data (SRP002475) was aligned with Bowtie. Peaks were identified by MACS and visualized using IGB. PDEF/Twist1 expression data was extracted from GSE16560. GraphPad was used to generate KM survival analysis of PCa patients. Our results show that PDEF expression is limited to epithelial/luminal cells of the prostatic glands. We observed that expression of Twist1 was down regulated in PC3 cells following PDEF expression. Analysis of gene expression data from our microarray studies revealed that PDEF re-expression was associated with negative enrichment of gene sets involved with cell migration and positive enriched of gene sets involved with epithelial/luminal differentiation. Chip-seq analysis revealed a binding of PDEF to KRT8/18 promoter region. These data suggest that PDEF inhibits core metastasis related genes through promoting a program of luminal/epithelial differentiation. In clinical samples of PCa, expression of PDEF was inversely associated, while expression of Twist1 was positively associated with Gleason grade. PDEF and Twist1 was able to predict patient survival, moreover integrated PDEF and Twist1 expression was able to better predict PCa patient survival as compared to PDEF or Twist1 alone. PDEF inhibits cell migration and metastasis in part by down-regulating Twist1 level and promoting luminal/epithelial differentiation. Loss of PDEF combined with gain of Twist1 expression may serve as a potential biomarker set for distinguishing lethal PCa from an indolent disease. Additional studies are underway to gain further insights into the role of PDEF in PCa progression and metastasis. Acknowledgement: FWCC support and Chair commitment funds (Koul H). Citation Format: Fengtian Wang, Sweaty Koul, Prakash Srinivasan Timiri Shanmugam, Qin Dong, Hari K. Koul. PDEF promote prostate cancer luminal/epithelial differentiation and inhibit tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3525. doi:10.1158/1538-7445.AM2017-3525
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