Abstract C25: Hsp27 is required for EGF-induced epithelial to mesenchymal transition in prostate cancer

Prostate cancer (PCa) is the most common cancer and the second leading cause cancer death in North American men. Understanding the molecular mechanisms underlying metastatic PCa development is essential to decrease morbidity and mortality. An important determinant for metastasis is epithelial to mesenchymal transition (EMT). We show that the molecular chaperone Hsp27 drives EMT in PCa cells by decreasing epithelial cell markers, upregulating mesenchymal markers and enhancing cell migration and MMP-9 activity. Mechanistically, Hsp27 is required for EMT induced by epidermal growh factor (EGF) via modulation of the beta-catenin/Slug signaling pathway. Hsp27 knockdown induces sequestration of beta-catenin in the cytoplasm by increasing its binding to GSK3beta and abrogating EGF induced beta-catenin nuclear translocation. Additionally, by decreasing the nuclear translocation of beta-catenin, Hsp27 knockdown decreases the binding of beta-catenin to the Slug promoter, thereby abrogating its transcriptional activity. As Slug is known to be a critical factor in EMT induction, we confirmed the role of Hsp27 in EGF mediated EMT using Hsp27 knockdown. To address a role for Hsp27 in promoting aggressive PCa in vivo , Hsp27 was suppressed in a murine model of PCa using the antisense drug OGX-427 (currently in phase II clinical trials). We found OGX-427 treatment significantly reduces tumor cell metastasis in mice, and moreover, decreases circulating tumor cell counts in patients with castration resistant prostate cancer. This study defines a role for Hsp27 as a critical regulator of EGF dependent EMT and highlights Hsp27 is an attractive anti-cancer target for metastatic PCa. Citation Format: Thomas Cordonnier, Jennifer L. Bishop, Masaki Shiota, Ario Takeuchi, Ka Mun Nip, Martin Gleave, Amina Zoubeidi. Hsp27 is required for EGF-induced epithelial to mesenchymal transition in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C25.