LAUSR

Background: The Hippo TEAD-transcriptional regulators YAP1 and TAZ play essential role in cancer cell growth and metastasis. However, the function of YAP1 and TAZ in prostate cancer is not well characterized. We discovered that expression of PDEF is decreased during prostate cancer progression and re-expression of PDEF limits prostate cancer metastasis in part by promoting luminal epithelial phenotype, but mechanisms of PDEF action are not completely understood. In the present study, we evaluated the effects of the SPDEF on YAP1/TAZ levels and expression of YAP1/TAZ regulated genes in prostate cancer (PCa) cells. We also evaluated expression of SPDEF, YAP1, TAZ and YAPTAZZ-Tead regulated genes in clinical cohorts of prostate cancer patients. Material & Method: Prostate cancer (PC3 and DU145) cells were transfected with PDEF or respective vector control. shRNA was used to knock down SPDEF in AR positive and androgen responsive LNCaP cells. Protein levels were analyzed by western blotting. Gene expression was monitored by microarray analysis/RNA seq and confirmed by RTPCR assays. Cell migration and invasion were measured by scratch wound healing and by trans well migration though Matrigel assays respectively. We analyzed publicly available gene expression data in several prostate cancer cohorts. Results: We observed that the two well-characterized metastatic PCa cells (PC3 and DU145 cells) express both YAP1 and TAZ, but do not express SPDEF. Expression of PDEF in PC3 and DU145 cells resulted in an increased phospho-YAP1 and phospho-TAZ protein levels and inhibition of YAP1/TAZ target genes, as compared to the respective vector control, directly demonstrating that PDEF plays a critical role in modulating YAP1/TAZ-TEAD transcriptional activity, and by extension in the regulation of the Hippo pathway. Analysis of publicly available PCa data sets revealed a significant increase in TAZ mRNA levels in prostate cancer tissues as compared to normal prostate tissues (p=4.95E-08). Furthermore, we also found a significant gradual increase in TAZ mRNA expression and concomitant decrease in YAP1 mRNA during disease progression and metastasis and in neuroendocrine PCa. Conclusions: Taken together these data suggest that SPDEF limits prostate cancer metastasis in part by targeting YAP1/TAZ driven transcriptional output. Citation Format: Hari K. Koul, Praveen K. Jaiswal, Suman Mohajan, Mousa Vatanmakanian, Fengtian Wang, Sweaty Koul. PDEF restricts prostate cancer cellular plasticity in part by modulating YAP1/TAZ-TEAD transcriptional network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1457.