title: Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer.
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-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 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.
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bishop
authors.forename: Ka Mun
authors.initials: KM
authors.lastname: Nip
authors.forename: Anousheh
authors.initials: A
authors.lastname: Zardan
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Thomas
authors.initials: T
authors.lastname: Cordonnier
authors.forename: Eliana
authors.initials: E
authors.lastname: Beraldi
authors.forename: Jenny
authors.initials: J
authors.lastname: Bazov
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Kim
authors.initials: K
authors.lastname: Chi
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D055551:HSP27 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics
chemical_list: D055551:HSP27 Heat-Shock Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D051879:Twist-Related Protein 1