Protein kinase D1 (PKD1) Mediated Rrepression of Epithelial-Mesenchymal Transition (EMT) in Prostate Cancer (PC)

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Abstract:
About 90% of all cancer deaths, including prostate cancer, arises from the metastatic spread of primary tumors. Current therapies for metastatic tumors are often ineffective. Therefore, understanding of tumor metastasis is critical to provide strategy for future therapies. Epithelial mesenchymal transition (EMT) has been described as an important step in cancer progression contributing to metastasis. Several epithelial markers including cell adhesion protein E-cadherin are characteristically lost during EMT with concomitant new expression of mesenchymal markers such as vimentin and N-cadherin. Several transcription factors, including Snail and Twister, repress E-cadherin expression. We previously showed that protein kinase D1 (PKD1), a serine-threonine kinase, is down regulated in advanced prostate cancer and interacts with E-cadherin. In this study, we demonstrate that knockdown of PKD1 or E-cadherin by RNA interference (RNAi) can induce expression of EMT markers, Vimentin, Fibronectin and N-cadherin in prostate cancer cells; over expression of PKD1 represses expression of EMT markers and induces expression of E-cadherin and beta-catenin, decreases cell motility and increases cell aggregation. Snail, but not Twister, is responsible for induction the expression of Vimentin and N-cadherin in PC. We demonstrate that PKD1 directly binds to Snail by yeast two-hybrid test and co-immunoprecipitation and phosphorylates Snail at S11, which influences nuclear export of Snail and E-cadherin expression. These results suggest that PKD1 may prevent EMT by repressing Snail function. Combined with our previous finding that PKD1 is down regulated in advanced prostate cancer, we propose that PKD1 is a novel EMT repressor, which may be mediated by Snail. Understanding the molecular mechanism of PKD1 function in cells identifies novel targets for therapeutic targeting and contributes to novel biomarker discovery.

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