Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or VSports app下载. mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

Review
. 2019 Dec 2;132(23):jcs235127.
doi: 10.1242/jcs.235127.

Molecular regulation of Snai2 in development and disease

Wenhui Zhou  1   2 , Kayla M Gross  1   2 , Charlotte Kuperwasser  3   2
Affiliations
Review

"V体育2025版" Molecular regulation of Snai2 in development and disease

Wenhui Zhou et al. J Cell Sci. .

Abstract (VSports最新版本)

The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis VSports手机版. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease. .

Keywords: Cancer; Development; Slug. V体育安卓版.

PubMed Disclaimer

Conflict of interest statement

Competing interestsC VSports最新版本. K. is a shareholder of Naveris, Inc. and a member of its scientific board of advisors.

Figures

Fig. 1. The molecular anatomy of the transcription factor Snai2. The transcription factor (TF) Snai2 is a well-conserved member of the Snail family. It contains several protein motifs characteristic of this TF family, such as a SNAG domain at the N-terminus and consecutive zinc finger domains at the C-terminus. These domains are particularly critical for Snai2’s role as a transcriptional regulator. The five C-terminal zinc finger domains of Snai2 bind to E-box consensus motifs in gene regulatory regions, while chromatin regulators, such as CtBP1, HDAC1/2, LSD1 and PRC2, are recruited via the SNAG domain (Bai et al., 2017; Phillips et al., 2014; Tien et al., 2015). Through this recruitment of epigenetic silencers, Snai2 facilitates transcriptional repression of its target genes. The SLUG domain also impacts Snai2 function. A variety of proteins, such as GSK3β, β-Trcp1, CHIP, FBXL14, MDM2, CDK2, p14Arf and SIRT2, can facilitate the deposition of post-translational modifications (PTM), including phosphorylation, ubiquitylation and acetylation, on SLUG domain residues that can dictate its proteolytic turnover or cellular localization (Hemavathy et al., 2000; Molina-Ortiz et al., 2012; Sefton et al., 1998; Zhou et al., 2016).
Fig. 1.
The molecular anatomy of the transcription factor Snai2. The transcription factor (TF) Snai2 is a well-conserved member of the Snail family. It contains several protein motifs characteristic of this TF family, such as a SNAG domain at the N-terminus and consecutive zinc finger domains at the C-terminus. These domains are particularly critical for Snai2’s role as a transcriptional regulator. The five C-terminal zinc finger domains of Snai2 bind to E-box consensus motifs in gene regulatory regions, while chromatin regulators, such as CtBP1, HDAC1/2, LSD1 and PRC2, are recruited via the SNAG domain (Bai et al., 2017; Phillips et al., 2014; Tien et al., 2015). Through this recruitment of epigenetic silencers, Snai2 facilitates transcriptional repression of its target genes. The SLUG domain also impacts Snai2 function. A variety of proteins, such as GSK3β, β-Trcp1, CHIP, FBXL14, MDM2, CDK2, p14Arf and SIRT2, can facilitate the deposition of post-translational modifications (PTM), including phosphorylation, ubiquitylation and acetylation, on SLUG domain residues that can dictate its proteolytic turnover or cellular localization (Hemavathy et al., 2000; Molina-Ortiz et al., 2012; Sefton et al., 1998; Zhou et al., 2016).
Fig. 2. The diversity of Snai2 function in development and tumorigenesis. As an EMT-TF, Snai2 represents a central convergence point of signaling processes to facilitate key morphogenic events during embryonic development. Such functions of Snai2, in addition to its expression in adult tissues, suggest that it is capable of regulating stem and progenitor cell biology beyond early development. Indeed, Snai2 function has been shown to be integral to maintaining adult stem cell compartments in the hematopoietic system, mammary gland, epidermis and mesenchymal tissues (Guo et al., 2012; Kim et al., 2010; Mistry et al., 2014; Nassour et al., 2012; Pérez-Losada et al., 2002; Phillips et al., 2014; Seki et al., 2003; Soleimani et al., 2012; Sun et al., 2010; Ye et al., 2015). Aside from conferring self-renewal and regenerative functions, Snai2 also regulates other aspects of stem and progenitor cell biology, such as lineage commitment and differentiation decisions, proliferative potential and cell survival, within many of these tissue compartments through additional mechanisms (Castillo-Lluva et al., 2015; Gross et al., 2019; Guo et al., 2012; Inoue et al., 2002; Kim et al., 2010; Lolli et al., 2014; Mistry et al., 2014; Nassour et al., 2012; Pérez-Losada et al., 2002; Phillips et al., 2014; Seki et al., 2003; Soleimani et al., 2012; Sun et al., 2010; Tang et al., 2016b; Wu et al., 2005). Importantly, Snai2 performs these functions not only in normal adult tissues but also in contexts of cancer. For example, while Snai2 is an important suppressor of apoptosis in normal hematopoietic stem cells, this function promotes therapeutic resistance in cancer cells (Arienti et al., 2013; Chang et al., 2011; Dong et al., 2016; Haslehurst et al., 2012; Jiang et al., 2016; Kurrey et al., 2009; Vitali et al., 2008; Wu et al., 2005). Emerging evidence has additionally highlighted a role for Snai2 in vascular biology. Snai2 facilitates vascular remodeling during pulmonary hypertension by altering expression of genes involved vascular smooth muscle differentiation, proliferation and migration (Coll-Bonfill et al., 2016). Snai2 also controls endothelial cell (EC) behavior during angiogenesis and osteogenic differentiation of ECs during vascular calcification, suggesting that Snai2 may be a key regulator involved in vascular disease.
Fig. 2.
The diversity of Snai2 function in development and tumorigenesis. As an EMT-TF, Snai2 represents a central convergence point of signaling processes to facilitate key morphogenic events during embryonic development. Such functions of Snai2, in addition to its expression in adult tissues, suggest that it is capable of regulating stem and progenitor cell biology beyond early development. Indeed, Snai2 function has been shown to be integral to maintaining adult stem cell compartments in the hematopoietic system, mammary gland, epidermis and mesenchymal tissues (Guo et al., 2012; Kim et al., 2010; Mistry et al., 2014; Nassour et al., 2012; Pérez-Losada et al., 2002; Phillips et al., 2014; Seki et al., 2003; Soleimani et al., 2012; Sun et al., 2010; Ye et al., 2015). Aside from conferring self-renewal and regenerative functions, Snai2 also regulates other aspects of stem and progenitor cell biology, such as lineage commitment and differentiation decisions, proliferative potential and cell survival, within many of these tissue compartments through additional mechanisms (Castillo-Lluva et al., 2015; Gross et al., 2019; Guo et al., 2012; Inoue et al., 2002; Kim et al., 2010; Lolli et al., 2014; Mistry et al., 2014; Nassour et al., 2012; Pérez-Losada et al., 2002; Phillips et al., 2014; Seki et al., 2003; Soleimani et al., 2012; Sun et al., 2010; Tang et al., 2016b; Wu et al., 2005). Importantly, Snai2 performs these functions not only in normal adult tissues but also in contexts of cancer. For example, while Snai2 is an important suppressor of apoptosis in normal hematopoietic stem cells, this function promotes therapeutic resistance in cancer cells (Arienti et al., 2013; Chang et al., 2011; Dong et al., 2016; Haslehurst et al., 2012; Jiang et al., 2016; Kurrey et al., 2009; Vitali et al., 2008; Wu et al., 2005). Emerging evidence has additionally highlighted a role for Snai2 in vascular biology. Snai2 facilitates vascular remodeling during pulmonary hypertension by altering expression of genes involved vascular smooth muscle differentiation, proliferation and migration (Coll-Bonfill et al., 2016). Snai2 also controls endothelial cell (EC) behavior during angiogenesis and osteogenic differentiation of ECs during vascular calcification, suggesting that Snai2 may be a key regulator involved in vascular disease.
Fig. 3. Overview of Snai2 regulation spanning from transcript to protein level. Snai2 levels are strictly regulated in normal tissues by multiple transcriptional, post-transcriptional and post-translational control mechanisms. SNAI2 transcription is controlled by many signaling pathways fundamental to developmental processes, including TGFβ, growth factors, Notch and Wnt signaling. Either through these known pathways or other mechanisms, its transcription is impacted or directly facilitated by a variety of transcriptional activators and repressors, as well as chromatin remodeling factors. At the post-transcriptional level, the expression level or stability of the SNAI2 gene product can be regulated by several known microRNAs or RNA-binding proteins. While not much is currently known about how Snai2 is regulated at the translational level, a wide array of post-translational modifier proteins have been established as critical regulators of Snai2 proteolytic turnover, cellular localization and biological function. Phosphorylation and ubiquitylation are the most abundant modifications made by these regulators, but recent findings have shown that Snai2 can also undergo sumolyation and acetylation, suggesting that post-translational modifications of Snai2 capable of regulating its stability and activity may be more diverse than previously thought.
Fig. 3.
Overview of Snai2 regulation spanning from transcript to protein level. Snai2 levels are strictly regulated in normal tissues by multiple transcriptional, post-transcriptional and post-translational control mechanisms. SNAI2 transcription is controlled by many signaling pathways fundamental to developmental processes, including TGFβ, growth factors, Notch and Wnt signaling. Either through these known pathways or other mechanisms, its transcription is impacted or directly facilitated by a variety of transcriptional activators and repressors, as well as chromatin remodeling factors. At the post-transcriptional level, the expression level or stability of the SNAI2 gene product can be regulated by several known microRNAs or RNA-binding proteins. While not much is currently known about how Snai2 is regulated at the translational level, a wide array of post-translational modifier proteins have been established as critical regulators of Snai2 proteolytic turnover, cellular localization and biological function. Phosphorylation and ubiquitylation are the most abundant modifications made by these regulators, but recent findings have shown that Snai2 can also undergo sumolyation and acetylation, suggesting that post-translational modifications of Snai2 capable of regulating its stability and activity may be more diverse than previously thought.
See this image and copyright information in PMC

References

    1. Ambs, S., Prueitt, R. L., Yi, M., Hudson, R. S., Howe, T. M., Petrocca, F., Wallace, T. A., Liu, C.-G., Volinia, S., Calin, G. A., et al. (2008). Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 68, 6162-6170. 10.1158/0008-5472.CAN-08-0144 - DOI - PMC - PubMed
    1. Arienti, C., Tesei, A., Carloni, S., Ulivi, P., Romeo, A., Ghigi, G., Menghi, E., Sarnelli, A., Parisi, E., Silvestrini, R., et al. (2013). SLUG silencing increases radiosensitivity of melanoma cells in vitro. Cell. Oncol. 36, 131-139. 10.1007/s13402-012-0120-6 - DOI - PubMed
    1. Bai, J.-W., Chen, M.-N., Wei, X.-L., Li, Y.-C., Lin, H.-Y., Chen, M., Li, J.-W., Du, C.-W., Man, K. and Zhang, G.-J. (2017). The zinc-finger transcriptional factor Slug transcriptionally downregulates ERα by recruiting lysine-specific demethylase 1 in human breast cancer. Oncogenesis 6, e330. 10.1038/oncsis.2017.38 - DOI - PMC - PubMed
    1. Barrallo-Gimeno, A. (2005). The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151-3161. 10.1242/dev.01907 - "VSports手机版" DOI - PubMed
    1. Bhat-Nakshatri, P., Appaiah, H., Ballas, C., Pick-Franke, P., Goulet, R., Badve, S., Srour, E. F. and Nakshatri, H. (2010). SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer 10, 411. 10.1186/1471-2407-10-411 - DOI - PMC - PubMed

"VSports" Publication types

MeSH terms

V体育ios版 - Substances

LinkOut - more resources