Hsp27 regulates EGF/β-catenin mediated epithelial to mesenchymal transition in prostate cancer

Increased expression of the molecular chaperone Hsp27 is associated with the progression of prostate cancer (PCa) to castration-resistant disease, which is lethal due to metastatic spread of the prostate tumor. Metastasis requires epithelial to mesenchymal transition (EMT), which endows cancer cells with the ability to disseminate from the primary tumor and colonize new tissue sites. A wide variety of secreted factors promote EMT, and while overexpression and constitutive activation of epidermal growth factor (EGF) signaling is associated with poor prognosis of PCa, a precise role of EGF in PCa progression to metastasis remains unclear. Here, we show that Hsp27 is required for EGF-induced cell migration, invasion and MMPs activity as well as the expression of EMT markers including Fibronectin, Vimentin and Slug with concomitant decrease of E-cadherin. Mechanistically, we found that Hsp27 is required for EGF-induced AKT and GSK3 phosphorylation and -catenin nuclear translocation. Moreover, silencing Hsp27 decreases EGF dependent phosphorylation of -catenin on tyrosine 142 and 654, enhances -catenin ubiquitination and degradation, prevents -catenin nuclear translocation and binding to the Slug promoter. These data suggest that Hsp27 is required for EGF-mediated EMT via modulation of the -catenin/Slug signaling pathway. Together, our findings underscore the importance of Hsp27 in EGF induced EMT in PCa and highlight the use of Hsp27 knockdown as a useful strategy for patients with advanced disease. What's new? Androgen withdrawal remains the most effective therapy for patients with prostate cancer. More than 80% of patients respond initially; however, most patient progress with incurable metastatic castrate resistant prostate cancer, characterized by increases in expression of the molecular chaperone Hsp27 as well as activation of the EGFR pathway. In this study, the authors found that silencing Hsp27 abrogates EGF induced epithelial to mesenchymal transition, a process essential to tumor metastasis, through inhibition of -catenin phosphorylation and ubiquitination. Since targeting Hsp27 using antisense therapy is currently in phase II clinical trials, this study provides a mechanistic rational behind targeting Hsp27 to prevent metastasis in CRPC patients.