title: Hsp27 regulates EGF/β-catenin mediated epithelial to mesenchymal transition in prostate cancer.
abstract: Increased expression of the molecular chaperone Hsp27 is associated with the progression of prostate cancer (PCa) to castration-resistant disease, which is lethal due to metastatic spread of the prostate tumor. Metastasis requires epithelial to mesenchymal transition (EMT), which endows cancer cells with the ability to disseminate from the primary tumor and colonize new tissue sites. A wide variety of secreted factors promote EMT, and while overexpression and constitutive activation of epidermal growth factor (EGF) signaling is associated with poor prognosis of PCa, a precise role of EGF in PCa progression to metastasis remains unclear. Here, we show that Hsp27 is required for EGF-induced cell migration, invasion and MMPs activity as well as the expression of EMT markers including Fibronectin, Vimentin and Slug with concomitant decrease of E-cadherin. Mechanistically, we found that Hsp27 is required for EGF-induced AKT and GSK3β phosphorylation and β-catenin nuclear translocation. Moreover, silencing Hsp27 decreases EGF dependent phosphorylation of β-catenin on tyrosine 142 and 654, enhances β-catenin ubiquitination and degradation, prevents β-catenin nuclear translocation and binding to the Slug promoter. These data suggest that Hsp27 is required for EGF-mediated EMT via modulation of the β-catenin/Slug signaling pathway. Together, our findings underscore the importance of Hsp27 in EGF induced EMT in PCa and highlight the use of Hsp27 knockdown as a useful strategy for patients with advanced disease.
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cordonnier
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bishop
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Ka Mun
authors.initials: KM
authors.lastname: Nip
authors.forename: Daksh
authors.initials: D
authors.lastname: Thaper
authors.forename: Sepideh
authors.initials: S
authors.lastname: Vahid
authors.forename: Devon
authors.initials: D
authors.lastname: Heroux
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D055551:HSP27 Heat-Shock Proteins / Q000502:physiology*; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018832:Molecular Chaperones; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D004815:Epidermal Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: EGF; EMT; Hsp27; prostate cancer; β-catenin