Molecular and Cellular Pathobiology Clusterin Mediates TGF-b–Induced Epithelial–Mesenchymal Transition andMetastasis via Twist1 in Prostate Cancer Cells

TGF-b promotes epithelial–mesenchymal transition (EMT) and induces clusterin (CLU) expression, linking these genes to cancermetastasis. CLU is a pleiotropicmolecular chaperone that confers survival and proliferative advantage to cancer cells. However, the molecular mechanisms by which TGF-b regulates CLU expression and CLU affects metastasis remain unknown. In this study, we report that the transcription factor Twist1 mediates TGF-b–induced CLU expression. By binding to E-boxes in the distal promoter region of CLU gene, Twist1 regulated basal and TGF-b–induced CLU transcription. In addition, CLU reduction reduced TGF-b induction of the mesenchymal markers, N-cadherin and fibronectin, thereby inhibiting the migratory and invasive properties induced by TGF-b. Targeted inhibition of CLU also suppressedmetastasis in an in vivomodel. Taken together, our findings indicate that CLU is an important mediator of TGF-b–induced EMT, and suggest that CLU suppression may represent a promising therapeutic option for suppressing prostate cancer metastatic progression. Cancer Res; 72(20); 5261–72. 2012 AACR