TY - JOUR
T1 - Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer
AU - Shiota, Masaki
AU - Bishop, Jennifer L.
AU - Nip, Ka Mun
AU - Zardan, Anousheh
AU - Takeuchi, Ario
AU - Cordonnier, Thomas
AU - Beraldi, Eliana
AU - Bazov, Jenny
AU - Fazli, Ladan
AU - Chi, Kim
AU - Gleave, Martin
AU - Zoubeidi, Amina
PY - 2013/5/15
Y1 - 2013/5/15
N2 - Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-tomesenchymal 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 prostate cancer, whereas its attenuation reverses EMT and decreases cell migration, invasion, and matrix metalloproteinase 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 patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6-dependent and IL-6-independent EMT, validating this chaperone as a therapeutic target to treat metastatic prostate cancer. Cancer Res; 73(10); 3109-19.
AB - Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-tomesenchymal 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 prostate cancer, whereas its attenuation reverses EMT and decreases cell migration, invasion, and matrix metalloproteinase 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 patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6-dependent and IL-6-independent EMT, validating this chaperone as a therapeutic target to treat metastatic prostate cancer. Cancer Res; 73(10); 3109-19.
UR - http://www.scopus.com/inward/record.url?scp=84877855030&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877855030&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-3979
DO - 10.1158/0008-5472.CAN-12-3979
M3 - Article
C2 - 23492367
AN - SCOPUS:84877855030
SN - 0008-5472
VL - 73
SP - 3109
EP - 3119
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -
