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

Cancer Res. 2012 Oct 15;72(20):5261-72. doi: 10.1158/0008-5472.CAN-12-0254. Epub 2012 Aug 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Clusterin / genetics
  • Clusterin / physiology*
  • DNA Primers
  • Epithelial-Mesenchymal Transition / physiology*
  • Humans
  • Male
  • Mice
  • Neoplasm Metastasis*
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / physiology*
  • Twist-Related Protein 1 / physiology*


  • Clusterin
  • DNA Primers
  • Nuclear Proteins
  • TWIST1 protein, human
  • Transforming Growth Factor beta
  • Twist-Related Protein 1