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Review
. 2014 Aug 2;33(1):62.
doi: 10.1186/s13046-014-0062-0.

Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention

Samantha Kaufhold, Benjamin Bonavida
Review

Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention

Samantha Kaufhold et al. J Exp Clin Cancer Res. .

Abstract

Snail1 is the founding member of the Snail superfamily of zinc-finger transcription factors, which also includes Snail2 (Slug) and Snail3 (Smuc). The superfamily is involved in cell differentiation and survival, two processes central in cancer research. Encoded by the SNAI1 gene located on human chromosome 20q13.2, Snail1 is composed of 264 amino acids and usually acts as a transcriptional repressor. Phosphorylation and nuclear localization of Snail1, governed by PI3K and Wnt signaling pathways crosstalk, are critical in Snail1's regulation. Snail1 has a pivotal role in the regulation of epithelial-mesenchymal transition (EMT), the process by which epithelial cells acquire a migratory, mesenchymal phenotype, as a result of its repression of E-cadherin. Snail1-induced EMT involves the loss of E-cadherin and claudins with concomitant upregulation of vimentin and fibronectin, among other biomarkers. While essential to normal developmental processes such as gastrulation, EMT is associated with metastasis, the cancer stem cell phenotype, and the regulation of chemo and immune resistance in cancer. Snail1 expression is a common sign of poor prognosis in metastatic cancer, and tumors with elevated Snail1 expression are disproportionately difficult to eradicate by current therapeutic treatments. The significance of Snail1 as a prognostic indicator, its involvement in the regulation of EMT and metastasis, and its roles in both drug and immune resistance point out that Snail1 is an attractive target for tumor growth inhibition and a target for sensitization to cytotoxic drugs.

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Figures

Figure 1
Figure 1
Amino acid sequences:human and mouse. This figure provides the human Snail1 amino acid sequence. The second representation of the sequence has important features such as phosphorylation sites and zinc fingers highlighted in various colors. 1) Purple indicates nuclear localization signals 2) blue is motif 1 for GSK-3β-mediated phosphorylation 3) green is motif 2 for GSK-3β-mediated phosphorylation 4) yellow is the PAK1 phosphorylation site and 5) gray denotes the zinc-finger region. In addition, human Snail2 (Slug) and mouse Snail1 amino acid sequences are shown for comparison to the human Snail1 sequence. Human Slug is 48% identical to human Snail1, and mouse Snail1 is 88% identical to human Snail1. The sequence alignments were run through BLAST [9].
Figure 2
Figure 2
Regulation at the Snail1 promoter. This figure depicts the regulatory interactions at the human Snail1 promoter. The central line represents the base-paired sequence, with -750 to -1 bp shown. The relative locations of interactions with various transcription factors are then spatially compared using blocks to represent each regulator’s binding site. Each block, with the base pairs involved denoted at the top, shows where that particular protein binds the Snail1 promoter.
Figure 3
Figure 3
Snail1 stability and localization. This figure shows the effects of GSK-3β and PAK1-mediated phosphorylation on Snail1 stability and subcellular localization. The outer circle represents the cell membrane, and the inner circle represents the nucleus. Nuclear Snail1 is phosphorylated by GSK-3β at motif 2 and is consequently exported from the nucleus. If Snail1 remains in the cytoplasm, it is ultimately ubiquitinated and degraded. By contrast, phosphorylation by PAK1 favors the nuclear localization of Snail1, which increases its stability.
Figure 4
Figure 4
Structures of chemical inhibitors targeting Snail1. A) GN 25 and GN 29 [175]B) Co(III)-Ebox [176]C) Tranylcypromine [183]D) Trichostatin A [184]E) Pargyline [185]F) LBH589 [186] and G) Entinostat [187].
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