Clusterin mediates TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells.
TGF-β promotes epithelial-mesenchymal transition (EMT) and induces clusterin (CLU) expression, linking these genes to cancer metastasis. CLU is a pleiotropic molecular chaperone that confers survival and proliferative advantage to cancer cells. However, the molecular mechanisms by which TGF-β regulates CLU expression and CLU affects metastasis remain unknown. In this study, we report that the transcription factor Twist1 mediates TGF-β-induced CLU expression. By binding to E-boxes in the distal promoter region of CLU gene, Twist1 regulated basal and TGF-β-induced CLU transcription. In addition, CLU reduction reduced TGF-β induction of the mesenchymal markers, N-cadherin and fibronectin, thereby inhibiting the migratory and invasive properties induced by TGF-β. Targeted inhibition of CLU also suppressed metastasis in an in vivo model. Taken together, our findings indicate that CLU is an important mediator of TGF-β-induced EMT, and suggest that CLU suppression may represent a promising therapeutic option for suppressing prostate cancer metastatic progression.
The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Masaki
M
Shiota
Anousheh
A
Zardan
Ario
A
Takeuchi
Masafumi
M
Kumano
Eliana
E
Beraldi
Seiji
S
Naito
Amina
A
Zoubeidi
Martin E
ME
Gleave
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D051152:Clusterin / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*
D051152:Clusterin; D017931:DNA Primers; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1