Hsp27 regulates epithelial mesenchymal transition, metastasis and circulating tumor cells in prostate cancer
Defining the mechanisms underlying metastatic progression of prostate cancer (PCa) may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-to-mesenchymal transition (EMT), and the mechanisms that control the process of EMT in cancer cells are still emerging. Here we report that the molecular chaperone Hsp27 (HSPB1) drives EMT in PCa while its attenuation reverses EMT and decreases cell migration, invasion and matrix metalloprotease activity. Mechanistically, silencing Hsp27 decreased IL-6 dependent STAT3 phosphorylation, nuclear translocation and STAT3 binding to the Twist promoter, suggesting that Hsp27 is required for IL-6 mediated EMT via modulation of STAT3/Twist signaling. We observed a correlation between Hsp27 and Twist in PCa patients, with Hsp27 and Twist expression each elevated in high grade PCa tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in Phase II trials, reduced tumor metastasis in a murine model of PCa. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant PCa in a Phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6 dependent and independent EMT, validating this chaperone as a therapeutic target to treat metastatic PCa.