STAT3 mediates TGF-β1-induced TWIST1 expression and prostate cancer invasion

• We report novel roles of STAT3 and HIF-1α in TWIST1 expression and prostate cancer progression.
• Both STAT3 and HIF-1α are required for TWIST1 expression and prostate cancer cell invasion.
• STAT3 stabilizes and accumulates HIF-1α in the nucleus to induce TWIST1 expression.
• TGF-β1 induces TWIST1 expression, leading to prostate cancer cell invasiveness.

TGF-β1 induces epithelial-mesenchymal transition (EMT) to stimulate cancer cell progression, and TWIST1 is a critical regulator of EMT. In the present study, we determined the underlying mechanisms of TGF-β1-induced TWIST1 expression and its effect on prostate cancer cell invasion. TGF-β1 stimulated STAT3 phosphorylation and HIF-1α expression. Silencing either STAT3 or HIF-1α efficiently attenuated TGF-β1-induced TWIST1 expression. Further ectopic expression of a dominant negative mutant of STAT3 reduced TGF-β1-induced TWIST1 expression. In addition, STAT3 and HIF-1α up-regulated TWIST1 expression by direct binding to a TWIST1 promoter. Strikingly, STAT3 also enhanced TGF-β1-induced TWIST1 expression through HIF-1α stabilization. Collectively, we demonstrate a mechanistic cascade of TGF-β1 up-regulating STAT3 activation and HIF-1α stabilization and subsequent TWIST1 expression, leading to prostate cancer invasion.