Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells

Abstract

Expression of Snail transcriptional factor is a determinant in the acquisition of a mesenchymal phenotype by epithelial tumor cells. However, the regulation of the transcription of this gene is still unknown. We describe here the characterization of a human SNAIL promoter that contains the initiation of transcription and regulates the expression of this gene in tumor cells. This promoter was activated in cell lines in response to agents that induce Snail transcription and the mesenchymal phenotype, as addition of the phorbol ester PMA or overexpression of integrin-linked kinase (ILK) or oncogenes such as Ha-ras or v-Akt. Although other regions of the promoter were required for a complete stimulation by Akt or ILK, a minimal fragment (À78/ þ 59) was sufficient to maintain the mesenchymal specificity. Activity of this minimal promoter and SNAIL RNA levels were dependent on ERK signaling pathway. NFjB/p65 also stimulated SNAIL transcription through a region located immediately upstream the minimal promoter, between À194 and À78. These results indicate that Snail transcription is driven by signaling pathways known to induce epithelial to mesenchymal transition, reinforcing the role of Snail in this process.

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

“…Snail1 mRNA expression is also regulated by RAS activation, but to a much lesser extent than Snail2. Snail1 expression has previously been reported to be induced by RAS and transforming growth factor-b (TGF-b) signalling through pathways involving both MAP kinase and PI3-kinase activities (Peinado et al, 2003;Barbera et al, 2004). With the ER:HRAS V12 system in HKe-3 cells, we showed that the Snail1 mRNA level was increased around 2.5-fold with 50 nM OHT after 3 days of induction (Figures 2h and i).…”

Mouse Snail Is a Target Gene for HIF

“…Transforming growth factor-b increases Snail expression during hair bud morphogenesis (37), while Notch upregulates Snail during cardiac valve development (38). Studies with cultured cells have identified several intracellular signaling pathways capable of inducing Snail transcription, including the MAPK, phosphoinositide-3-kinase (PI3K), integrinlinked kinase (ILK), and nuclear factor-kB (NFkB) pathways (39)(40)(41)(42). Several transcription factors have been linked to Snail induction, including Gli1 (43), early growth response 1 (EGR1; ref.…”

“…Several transcription factors have been linked to Snail induction, including Gli1 (43), early growth response 1 (EGR1; ref. 44), high mobility group AT-hook 2 (45), and NFkB (40,41). Response elements to some of …”

Gambogic acid inhibits TNF-α-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-κB signaling pathways

“…In addition, TNF-α-induced cell migration and invasion were associated with NF-κB-mediated stabilization of Snail [3,6] . Because NF-κB may bind to the human Snail promoter causing increased Snail expression [19] , we tested whether the regulation of Snail expression might be involved in the TNF-α-mediated migration and invasion of PC3 cells. A ChIP assay revealed that the NF-κB p65 subunit was constitutively bound to the Snail promoter, and this binding was increased upon NF-κB activation by TNF-α.…”

“…It was recently reported that transcription of Snail was regulated by the NF-κB pathway [6] . As a critical subunit of NF-κB, p65 can bind the human Snail promoter and increase Snail transcription [19] . To further determine the mechanisms underlying the regulatory effect of GA on TNF-α-induced cell invasion, we examined the DNA binding activity of NF-κB using a ChIP assay.…”