Snail2 is an Essential Mediator of Twist1-Induced Epithelial Mesenchymal Transition and Metastasis

TLDR

Carcinoma cells must attenuate cell–cell adhesion to metastasize, and transcription factors such as Twist1, Snail1, Snail2, ZEB1, and ZEB2 induce EMT to promote tumor dissemination. It is unknown whether these transcription factors function independently or coordinately to activate the EMT program. Twist1 binds an evolutionarily conserved E‑box on the Snail2 promoter to induce its transcription. Direct induction of Snail2 is essential for Twist1 to suppress E‑cadherin transcription, promote cell invasion and distant metastasis in mice, and the expression of Twist1 and Snail2 is highly correlated in human breast tumors, indicating they act together to drive EMT and metastasis. Cancer Res 71(1):245–54, ©2010 AACR.

Abstract

Abstract To metastasize, carcinoma cells must attenuate cell–cell adhesion to disseminate into distant organs. A group of transcription factors, including Twist1, Snail1, Snail2, ZEB1, and ZEB2, have been shown to induce epithelial mesenchymal transition (EMT), thus promoting tumor dissemination. However, it is unknown whether these transcription factors function independently or coordinately to activate the EMT program. Here we report that direct induction of Snail2 is essential for Twist1 to induce EMT. Snail2 knockdown completely blocks the ability of Twist1 to suppress E-cadherin transcription. Twist1 binds to an evolutionarily conserved E-box on the proximate Snail2 promoter to induce its transcription. Snail2 induction is essential for Twist1-induced cell invasion and distant metastasis in mice. In human breast tumors, the expression of Twist1 and Snail2 is highly correlated. Together, our results show that Twist1 needs to induce Snail2 to suppress the epithelial branch of the EMT program and that Twist1 and Snail2 act together to promote EMT and tumor metastasis. Cancer Res; 71(1); 245–54. ©2010 AACR.