Clusterin mediates TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells

Masaki Shiota, Anousheh Zardan, Ario Takeuchi, Masafumi Kumano, Eliana Beraldi, Seiji Naito, Amina Zoubeidi, Martin E. Gleave

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96 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5261-5272
Number of pages12
JournalCancer Research
Volume72
Issue number20
DOIs
Publication statusPublished - Oct 15 2012
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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