Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer

Masaki Shiota, Jennifer L. Bishop, Ka Mun Nip, Anousheh Zardan, Ario Takeuchi, Thomas Cordonnier, Eliana Beraldi, Jenny Bazov, Ladan Fazli, Kim Chi, Martin Gleave, Amina Zoubeidi

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122 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3109-3119
Number of pages11
JournalCancer Research
Volume73
Issue number10
DOIs
Publication statusPublished - May 15 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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  • Cite this

    Shiota, M., Bishop, J. L., Nip, K. M., Zardan, A., Takeuchi, A., Cordonnier, T., Beraldi, E., Bazov, J., Fazli, L., Chi, K., Gleave, M., & Zoubeidi, A. (2013). Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Research, 73(10), 3109-3119. https://doi.org/10.1158/0008-5472.CAN-12-3979