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

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. Ó2011 AACR.

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

“…Of note, the relative upregulation of SLUG/ SNAIL2 expression in the HER2 gene-amplified JIMT1 cells was comparable to the HER2-negative MDA-MB-231 mesenchymal cells, whereas the HER2-negative MDA-MB-468 basallike cells did not show an increase in the expression of SLUG/ SNAIL2. In a similar manner and in accordance with the ability of SLUG/SNAIL2 and TWIST1 to suppress the epithelial branch of the EMT program redundantly in a cooperative manner, 43 the relative expression of TWIST1 was increased by approximately 100-fold in the trastuzumab-resistant HER2 + SLUG + JIMT-1 cells compared with the trastuzumab-responsive HER2 + SLUG -SKBR3 cells. HER2-negative MDA-MB-468 basal cells showed no increase in the expression of TWIST.…”

Forced expression of Nanog with mRNA synthesized in vitro to evaluate the malignancy of HeLa cells through acquiring cancer stem cell phenotypes

“…In addition, the expression of Snail/Slug and Twist were also increased in Nanog overexpressing HeLa cells. It has been reported that Snail/Slug signaling regulates the EMT process (19). This evidence implies that Snail/Slug and Twist participate in regulating the EMT process to influence the metastasis of HeLa cells.…”

MicroRNA-124 inhibits cell proliferation and migration by regulating SNAI2 in breast cancer

“…SNAI2, a member of the snail family of C 2 H 2 -type zinc-finger transcription factors, promotes epithelial-mesenchymal transition and has antiapoptotic activity (48). These data demonstrate that SNAI2 is a direct target of miR-124, and that miR-124-mediated inhibition of SNAI2 is dependent on a conversed motif in the 3'-UTR of SNAI2.…”