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Link to original content: http://omim.org/entry/604238
Alternative titles; symbols
HGNC Approved Gene Symbol: SNAI1
Cytogenetic location: 20q13.13 Genomic coordinates (GRCh38) : 20:49,982,980-49,988,886 (from NCBI)
The zinc finger transcription factor 'snail' was first identified in Drosophila and, along with 'twist' (TWIST1; 601622), a basic helix-loop-helix transcription factor, is indispensable for mesoderm formation (Grau et al., 1984). Drosophila embryos homozygous for snail or twist mutations form no ventral furrow, fail to develop a mesoderm layer, and die early in embryogenesis. While twist functions as a positive regulator of mesoderm-specific genes, snail acts as a boundary repressor by downregulating the expression of ectodermal genes within the mesoderm. Snail is a member of the Drosophila Snail family of proteins. In vertebrates, only 2 members of the snail family of proteins are known, Snail and Slug (602150); see Sefton et al. (1998). Analysis of snail in vertebrates has confirmed its role in mesoderm formation.
Twigg and Wilkie (1999) isolated and characterized the human SNAI1 gene. A single transcript of 1.9 kb was detected in several human fetal tissues, with highest expression in kidney. The SNAI1 open reading frame encodes a deduced 264-amino acid protein containing 4 zinc finger motifs that show 87.1% identity to mouse Snai1.
By in situ hybridization of early mouse embryos undergoing epithelial-mesenchymal transitions, Cano et al. (2000) found that Snai1 is a repressor of mouse E-cadherin (192090) transcription, with expression of Snai1 inversely correlated with expression of E-cadherin. They also found strong evidence that abnormal expression of SNAI1 could underlie the tumorigenic conversion of epithelia associated with loss of E-cadherin expression through screening mouse and human cell lines and by in situ hybridization of primary human tumors undergoing malignant progression. By transfection experiments with several epithelial cell lines, they found that Snai1 overexpression leads to a dramatic conversion to a fibroblastic phenotype at the same time that E-cadherin expression is lost and tumorigenic and invasive properties are acquired. Batlle et al. (2000) found the identical inverse pattern of Snai1 and E-cadherin expression by Northern blot analysis of a panel of epithelial tumor cell lines. Likewise, they also found that exogenous expression of SNAI1 downregulates E-cadherin mRNA. Through transfection of antisense SNAI1, they observed that reduction in SNAI1 levels promotes a significant restoration of E-cadherin mRNA and protein. Through mutation analysis and gel retardation assays, Batlle et al. (2000) found that the 3 E boxes contained in the promoter region of E-cadherin cooperate in SNAI1-mediated E-cadherin repression.
By RT-PCR, Okubo et al. (2001) found that SNAI1 expression is higher in normal breast epithelial cell and stromal fibroblast cell lines than in breast cancer cell lines. They showed that SNAI1 interacts with a regulatory region near promoter I.3 of the human aromatase gene (107910), resulting in repression of promoter I.3 and in downregulation of aromatase expression in normal breast tissue.
Using retroviral transduction, Palmer et al. (2004) generated human SW480-ADH colon cancer cells that ectopically express mouse hemagglutinin-tagged Snai1 protein (SNAIL-HA). Overexpression of Snai1 in these cells resulted in lower vitamin D receptor (VDR; 601769) mRNA and protein expression and inhibited induction of E-cadherin and VDR by 1,25(OH)2D3. A 1,25(OH)2D3 analog inhibited tumor growth in immunodeficient mice injected with mock cells, but not in those injected with SNAIL-HA cells. In 32 paired samples of normal colon and tumor tissue from patients undergoing colorectal surgery, Palmer et al. (2004) found that high SNAI1 expression in tumor tissue correlated with downregulation of VDR and E-cadherin (p = 0.007 and 0.0073, respectively). Palmer et al. (2004) concluded that the balance between VDR and SNAI1 expression is critical for E-cadherin expression, which influences cell fate during colon cancer progression.
Vega et al. (2004) found that Snai1 regulated cell cycle progression in canine kidney cells transfected with mouse Snai1 and in mouse and chicken embryos. Snai1 also conferred resistance to cell death induced by withdrawal of survival factors and by proapoptotic signals.
Among 48 primary ovarian cancer (167000) tumors and corresponding metastases, Blechschmidt et al. (2008) found a significant association (p = 0.008) between reduced E-cadherin expression in the primary cancer tissue and shorter overall survival. Patients with decreased E-cadherin expression and increased SNAIL expression in the primary tumor showed a higher risk of death (p = 0.002). There was no significant difference in expression of E-cadherin or SNAIL between primary tumors and metastases. The findings were consistent with a role for E-cadherin and SNAIL in the behavior of metastatic cancer.
SNAIL1 is an unstable transcription factor that is phosphorylated by GSK3-beta (605004) in the nucleus, which triggers its nuclear export and subsequent ubiquitination and proteasomal degradation. Using human and mouse cell lines, Vinas-Castells et al. (2010) found that FBXL14 (609081) also directed ubiquitination and degradation of SNAIL1. FBXL14 interacted with SNAIL1 independent of GSK3-beta or phosphorylation of SNAIL1 and ubiquitinated 3 of 5 conserved lysines in the SNAIL1 N-terminal domain. In MCF-7 cells, hypoxia resulted in downregulation of FBXL14 and a subsequent increase in SNAIL1 protein levels. RNA interference experiments in mouse mammary carcinoma cells showed that hypoxia-induced Twist1 stimulation was necessary for Fbxl14 downregulation and stabilization of Snail1.
Using genetically engineered knockin reporter mouse lines, Ye et al. (2015) demonstrated that normal gland-reconstituting mammary stem cells residing in the basal layer of the mammary epithelium and breast tumor-initiating cells originating in the luminal layer exploit the paralogous epithelial-to-mesenchymal transition (EMT)-transcription factors Slug (602150) and Snail, respectively, which induce distinct EMT programs. Ye et al. (2015) cautioned that seemingly similar stem cell programs operating in tumor initiating cells and normal stem cells of the corresponding normal tissue are likely to differ significantly in their details.
Ocana et al. (2017) found that in mouse, Snail1 acts in a similar manner to Prrx1a (167420) in zebrafish and Prrx1 in the chick, driving left-right differential cell movements towards the midline, leading to a leftward displacement of the cardiac posterior pole through an actomyosin-dependent mechanism.
Zhao et al. (2018) found that ectopic expression of the phosphatase SCP4 (CTDSPL2; 618739) in MCF10A human mammary epithelial cells enhanced TGFB (TGFB1; 190180)-induced epithelial-mesenchymal transition and promoted cell migration through regulation of SNAIL. In contrast, knockdown of SCP4 attenuated these parameters. SCP4 bound directly to the N-terminal region of SNAIL and promoted SNAIL stability by blocking its polyubiquitination through dephosphorylation of ser96 and ser100.
The SNAI1 gene spans approximately 6.4 kb, contains 3 exons, and has a CpG island upstream of the coding sequence (11:Twigg and Wilkie, 1999).
By fluorescence in situ hybridization and radiation hybrid analysis, Twigg and Wilkie (1999) mapped the SNAI1 gene to human chromosome 20q13.1. They also isolated and sequenced an SNAI1 pseudogene (SNAI1P) and mapped it to 2q34.
Because of the involvement of heterozygous intragenic mutations and deletions of the TWIST gene as the cause of Saethre-Chotzen syndrome (101400), a craniosynostosis syndrome, and because of the complementary roles of twist and snail in early Drosophila development, Twigg and Wilkie (1999) studied the possible role of SNAI1 in syndromic and nonsyndromic craniosynostosis. Investigation of SNAI1 coding sequences by SSCP analysis excluded SNAI1 as a major disease gene in craniosynostosis. Similar results were reported by Paznekas et al. (1999).
Perez-Mancera et al. (2005) generated mice with tetracycline-repressible Snail transgene that increase Snail expression levels 20% above normal. These mice exhibited no morphologic alterations but developed both epithelial and mesenchymal tumors (leukemias). Suppression of the Snail transgene did not rescue the malignant phenotype, indicating that alterations induced by Snail are irreversible. Snail-transgenic murine embryonic fibroblasts (MEF) showed similar migratory ability to that of control MEFs; however, Snail-transgenic MEFs induced tumor formation in nude mice. Snail expression resulted in increased radioprotection in vivo, although it did not affect p53 (191170) regulation in response to DNA damage. In concert with these results, Snail expression was repressed following DNA damage in a p53-independent manner. Perez-Mancera et al. (2005) concluded that Snail may play essential roles in cancer development in mammals and thereby influence cell fate in the genotoxic stress response.
To avoid the early embryonic lethality of Snail-null mice, which likely results from defects in extraembryonic membranes, Murray and Gridley (2006) created mice with conditional deletion of the Snail gene. Conditional Snail knockout embryos survived to embryonic day 9.5, when they subsequently died of severe vascular defects. These embryos showed defects in left-right asymmetry, but unlike Snail-deleted frog and avian embryos, they showed no neural crest defects.
Batlle, E., Sancho, E., Franci, C., Dominguez, D., Monfar, M., Baulida, J., Garcia de Herreros, A. The transition factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biol. 2: 84-89, 2000. [PubMed: 10655587] [Full Text: https://doi.org/10.1038/35000034]
Blechschmidt, K., Sassen, S., Schmalfeldt, B., Schuster, T., Hofler, H., Becker, K.-F. The E-cadherin repressor snail is associated with lower overall survival of ovarian cancer patients. Brit. J. Cancer 98: 489-495, 2008. [PubMed: 18026186] [Full Text: https://doi.org/10.1038/sj.bjc.6604115]
Cano, A., Perez-Moreno, M. A., Rodrigo, I., Locascio, A., Blanco, M. J., del Barrio, M. G., Portillo, F., Nieto, M. A. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2: 76-83, 2000. [PubMed: 10655586] [Full Text: https://doi.org/10.1038/35000025]
Grau, Y., Carteret, C., Simpson, P. Mutations and chromosomal rearrangements affecting the expression of snail, a gene involved in embryonic patterning in Drosophila melanogaster. Genetics 108: 347-360, 1984. [PubMed: 17246230] [Full Text: https://doi.org/10.1093/genetics/108.2.347]
Murray, S. A., Gridley, T. Snail family genes are required for left-right asymmetry determination, but not neural crest formation, in mice. Proc. Nat. Acad. Sci. 103: 10300-10304, 2006. [PubMed: 16801545] [Full Text: https://doi.org/10.1073/pnas.0602234103]
Ocana, O. H., Coskun, H., Minguillon, C., Murawala, P., Tanaka, E. M., Galceran, J., Munoz-Chapuli, R., Nieto, M. A. A right-handed signaling pathway drives heart looping in vertebrates. Nature 549: 86-90, 2017. [PubMed: 28880281] [Full Text: https://doi.org/10.1038/nature23454]
Okubo, T., Truong, T. K., Yu, B., Itoh, T., Zhao, J., Grube, B., Zhou, D., Chen, S. Down-regulation of promoter I.3 activity of the human aromatase gene in breast tissue by zinc-finger protein, snail (SnaH). Cancer Res. 61: 1338-1346, 2001. [PubMed: 11245431]
Palmer, H. G., Larriba, M. J., Garcia, J. M., Ordonez-Moran, P., Pena, C., Peiro, S., Puig, I., Rodriguez, R., de la Fuente, R., Bernad, A., Pollan, M., Bonilla, F., Gamallo, C., Garcia de Herreros, A., Munoz, A. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nature Med. 10: 917-919, 2004. [PubMed: 15322538] [Full Text: https://doi.org/10.1038/nm1095]
Paznekas, W. A., Okajima, K., Schertzer, M., Wood, S., Jabs, E. W. Genomic organization, expression, and chromosome location of the human SNAIL gene (SNAI1) and a related processed pseudogene (SNAI1P). Genomics 62: 42-49, 1999. [PubMed: 10585766] [Full Text: https://doi.org/10.1006/geno.1999.6010]
Perez-Mancera, P. A., Perez-Caro, M., Gonzalez-Herrero, I., Flores, T., Orfao, A., Garcia de Herreros, A., Gutierrez-Adan, A., Pintado, B., Sagrera, A., Sanchez-Martin, M., Sanchez-Garcia, I. Cancer development induced by graded expression of Snail in mice. Hum. Molec. Genet. 14: 3449-3461, 2005. [PubMed: 16207734] [Full Text: https://doi.org/10.1093/hmg/ddi373]
Sefton, M., Sanchez, S., Nieto, M. A. Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development 125: 3111-3121, 1998. [PubMed: 9671584] [Full Text: https://doi.org/10.1242/dev.125.16.3111]
Twigg, S. R. F., Wilkie, A. O. M. Characterisation of the human snail (SNAI1) gene and exclusion as a major disease gene in craniosynostosis. Hum. Genet. 105: 320-326, 1999. [PubMed: 10543399] [Full Text: https://doi.org/10.1007/s004399900143]
Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., Fabregat, I., Nieto, M. A. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18: 1131-1143, 2004. [PubMed: 15155580] [Full Text: https://doi.org/10.1101/gad.294104]
Vinas-Castells, R., Beltran, M., Valls, G., Gomez, I., Garcia, J. M., Montserrat-Sentis, B., Baulida, J., Bonilla, F., Garcia de Herreros, A., Diaz, V. M. The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J. Biol. Chem. 285: 3794-3805, 2010. [PubMed: 19955572] [Full Text: https://doi.org/10.1074/jbc.M109.065995]
Ye, X., Tam, W. L., Shibue, T., Kaygusuz, Y., Reinhardt, F., Ng Eaton, E., Weinberg, R. A. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525: 256-260, 2015. [PubMed: 26331542] [Full Text: https://doi.org/10.1038/nature14897]
Zhao, Y., Liu, J., Chen, F., Feng, X.-H. C-terminal domain small phosphatase-like 2 promotes epithelial-to-mesenchymal transition via Snail dephosphorylation and stabilization. Open Biol. 8: 170274, 2018. Note: Electronic Article. [PubMed: 29618518] [Full Text: https://doi.org/10.1098/rsob.170274]