Affinage

SNAI2

Zinc finger protein SNAI2 · UniProt O43623

Length
268 aa
Mass
30.0 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNAI2 (Slug) is a C2H2 zinc-finger transcriptional repressor that drives epithelial-to-mesenchymal transition (EMT), neural crest development, and stem/progenitor cell programs by binding E-box motifs in target promoters and assembling co-repressor complexes (PMID:17344227, PMID:24297167, PMID:22567133). Sequence-specific DNA recognition requires intact zinc fingers ZF3 or ZF4, while transcriptional silencing is mediated through its N-terminal SNAG domain (recruiting NCoR) and central SLUG domain (recruiting CtBP1) (PMID:24297167, PMID:22567133). At target loci such as E-cadherin and cadherin6B, Slug nucleates chromatin-modifying machinery — Sin3A/HDAC, G9a, HDAC6/PRC2, and EZH2 — to deacetylate histones and deposit repressive H3K9 and H3K27 methylation marks (PMID:22986495, PMID:25617436, PMID:31432592, PMID:30541610). Beyond classical cadherin repression, Slug directly silences proapoptotic and tumor-suppressor genes including Puma, PTEN, and VDR, and activates SLC7A11 to suppress ferroptosis, collectively promoting cell survival, invasion, and metastasis (PMID:24830722, PMID:19502595, PMID:25728608, PMID:35220872). In development and tissue homeostasis it specifies the mammary stem cell state cooperatively with Sox9, controls epidermal progenitor differentiation, and is required for mesoderm-derived neural crest induction (PMID:22385965, PMID:25100569, PMID:21715424). Slug abundance and activity are tightly tuned by post-translational modifications: GSK-3β and cyclin E/CDK2 phosphorylation drives proteasomal degradation, SUMOylation enhances repressor activity by recruiting HDAC1, CBP acetylation stabilizes the protein, and opposing deubiquitinases (USP5, USP20 stabilizing; USP10 and the FBXO28 E3 ligase receptor destabilizing) set its steady-state level (PMID:22727060, PMID:24662826, PMID:30612578, PMID:32737855, PMID:30809294, PMID:32943575, PMID:29803676, PMID:37596321). Upstream, Slug is induced by Twist1, EGFR/ERK5, and SDF1α/CXCR4 signaling and repressed by ERα-HDAC1-NCoR and SNAI1-HDAC complexes (PMID:21199805, PMID:18716062, PMID:33106502, PMID:18588516, PMID:20101232, PMID:31165775). It additionally functions in DNA damage response signaling through the ATR-RPA32-CHK1 axis, in an autophagy-promoting feed-forward loop with FOXO3, and in angiogenesis by suppressing Dll4-Notch to maintain VEGFR2 expression (PMID:31291576, PMID:35271390, PMID:33106502). Homozygous SNAI2 deletions cause Waardenburg syndrome type 2 with neural-crest-derived auditory-pigmentary defects (PMID:12444107).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 Medium

    Established SNAI2 as a clinically relevant neural-crest gene whose loss causes a defined human syndrome, framing its developmental importance.

    Evidence Human genetics of homozygous SLUG deletions plus MITF promoter transactivation and Slugh×Kit genetic interaction

    PMID:12444107

    Open questions at the time
    • Molecular mechanism linking SLUG loss to specific lineage defects not resolved
    • Direct downstream targets in affected lineages not defined
  2. 2004 Medium

    Showed Slug functions as a pro-survival repressor of apoptosis, expanding its role beyond adhesion regulation.

    Evidence Gain/loss of function in cancer cells with proapoptotic target readouts and DNA-damage survival assays

    PMID:15314165

    Open questions at the time
    • Limited direct promoter-binding data for individual proapoptotic targets
    • Specific target genes only partially defined at this stage
  3. 2007 High

    Demonstrated direct sequence-specific repression in vivo, defining Slug as a bona fide E-box-binding repressor during neural crest EMT.

    Evidence Morpholino knockdown in chick embryos with in vivo/in vitro ChIP and EMSA on cadherin6B E-boxes

    PMID:17344227

    Open questions at the time
    • Co-repressor machinery at this locus not yet identified
    • Generalizability to other targets not tested here
  4. 2008 High

    Identified an upstream signaling input (EGFR/ERK5) and a hormonal repressive circuit (ERα-HDAC1-NCoR), placing Slug within receptor and nuclear-receptor signaling networks.

    Evidence ERK5 pharmacologic/shRNA perturbation with Slug mRNA and migration readouts; sequential ChIP confirming ERα-HDAC1-NCoR ternary complex at Slug promoter EREs

    PMID:18588516 PMID:18716062 PMID:20101232

    Open questions at the time
    • Direct kinase substrate relationship between ERK5 and Slug not established
    • How signaling integrates with degradation machinery unclear
  5. 2012 High

    Defined the domain logic of Slug repression and the chromatin complexes it assembles, and identified the mammary stem-cell program it controls.

    Evidence Domain mutagenesis with Co-IP of NCoR/CtBP1; PHD12-Sin3A/HDAC complex Co-IP and ChIP at Cad6b; mammary reconstitution assays for Slug/Sox9 cooperation

    PMID:22385965 PMID:22567133 PMID:22986495

    Open questions at the time
    • Context-dependence of complex choice not fully resolved
    • Structural basis of co-repressor selection not determined
  6. 2013 High

    Resolved the DNA-binding grammar of Slug, showing ZF3/ZF4 dependence distinguishes it from Snail1.

    Evidence Zinc-finger point mutants, protein-DNA modeling, luciferase and EMT assays on E-cadherin E2-box

    PMID:24297167

    Open questions at the time
    • Genome-wide binding consequences of ZF mutations not mapped
    • Co-factor recruitment dependence on specific fingers not tested
  7. 2014 High

    Established Slug as a node controlled by phospho-degradation cell-cycle coupling and SUMO stabilization, and identified key direct survival/tumor-suppressor targets.

    Evidence Cyclin E/CDK2 phospho-site mutagenesis with ubiquitylation and cell-cycle assays; p14ARF/SUMOylation mouse genetics; ChIP/rescue for Puma and PTEN repression

    PMID:24662826 PMID:24830722 PMID:24910389 PMID:25728608

    Open questions at the time
    • Interplay between competing PTMs on a single Slug molecule unresolved
    • E3 ligases mediating phospho-degron-dependent turnover not all identified here
  8. 2015 High

    Linked Slug to PRC2/EZH2-mediated repressive chromatin in neural crest and identified vimentin-scaffolded ERK phosphorylation as an EMT-initiating event.

    Evidence Co-IP and ChIP showing EZH2 interaction and H3K27me3 changes in Xenopus; vimentin-ERK scaffold Co-IP with Slug S87 mutagenesis

    PMID:25617436 PMID:25855378

    Open questions at the time
    • Whether Slug directly recruits PRC2 or acts indirectly not fully separated
    • Functional hierarchy among multiple phospho-sites not integrated
  9. 2018 Medium

    Mapped additional histone-modifying co-repressors (HDAC6/PRC2) and an antagonistic deubiquitinase (USP10) controlling Slug.

    Evidence Co-IP/ChIP for HDAC6-PRC2 at E-cadherin promoter; DUB siRNA screen with Co-IP and proteasome assays for USP10

    PMID:29803676 PMID:30541610

    Open questions at the time
    • Reciprocal validation of USP10-Slug interaction limited
    • Selectivity of HDAC6/PRC2 recruitment across cell types not established
  10. 2019 High

    Consolidated the deubiquitinase axis (USP5 stabilizing), the G9a-HDAC repressor complex, the SUMO-HDAC1 activity-enhancing mechanism, and a DNA damage response role.

    Evidence AP-MS/Co-IP/SPR/deubiquitination assays for USP5; Co-IP/ChIP for G9a-HDAC; SUMOylation reconstitution with HDAC1 recruitment; Snai2 knockout mice with ATR/RPA32/CHK1 phosphorylation analysis

    PMID:30612578 PMID:30809294 PMID:31291576 PMID:31432592

    Open questions at the time
    • Direct biochemical interaction of Slug with DDR components not reconstituted
    • How SUMO and ubiquitin marks are coordinated unresolved
  11. 2020 High

    Identified CBP acetylation as a stabilizing PTM, USP20 as a metastasis-promoting deubiquitinase, and defined the endothelial Slug-Dll4-Notch-VEGFR2 angiogenic axis.

    Evidence CBP HAT-domain Co-IP and in vitro acetylation; DUB cDNA/siRNA screens for USP20 with in vivo metastasis; Slug KO mice with Notch/VEGF epistasis in retinal angiogenesis

    PMID:32737855 PMID:32943575 PMID:33106502

    Open questions at the time
    • Combinatorial logic of acetylation, ubiquitination and SUMOylation not integrated
    • Direct Slug targets within the Dll4-Notch axis not all mapped
  12. 2022 High

    Revealed conserved noncanonical roles of Slug in autophagy (FOXO3 feed-forward loop via CRM1 export control) and ferroptosis suppression (SLC7A11 activation).

    Evidence Genome-wide screen, FOXO3 Co-IP and nuclear-export assays, Drosophila validation; SLC7A11 promoter ChIP/reporter with ferroptosis and xenograft assays

    PMID:35220872 PMID:35271390

    Open questions at the time
    • Whether Slug acts as activator versus repressor at distinct loci mechanistically unresolved
    • Conditions selecting autophagy versus EMT outputs unclear
  13. 2023 Medium

    Identified FBXO28 as a direct SCF E3 substrate receptor degrading Slug in a PKA-cooperative manner, refining the ubiquitin-proteasome control of Slug stability.

    Evidence Co-IP binding, ubiquitination assays, HCC metastasis models and clinical correlation

    PMID:37596321

    Open questions at the time
    • Degron recognized by FBXO28 not mapped
    • Mechanism of PKA cooperativity not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing post-translational modifications and context-specific co-repressor/co-activator choices are integrated to switch Slug between repressor and activator functions across tissues remains unresolved.
  • No unified structural or biochemical model of combinatorial PTM logic
  • Determinants of activator versus repressor target selection unknown
  • Genome-wide cofactor partition across cell types undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-1266738 Developmental Biology 5 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-5357801 Programmed Cell Death 3
Partners
CREBBPCTBP1EZH2FBXO28FOXO3NCOR1USP20USP5
Complex memberships
G9a-HDAC repressor complexHDAC6-PRC2 repressor complexSin3A/HDAC co-repressor complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Snail2 directly binds to clustered E-box motifs in the cadherin6B regulatory region and represses its transcription during neural crest EMT in vivo; morpholino-mediated Snail2 depletion in chick embryos derepressed cadherin6B within 30 minutes, and in vivo/in vitro biochemical assays confirmed direct binding. Morpholino knockdown, quantitative PCR, in vivo and in vitro chromatin immunoprecipitation/EMSA on cadherin6B promoter E-boxes Development High 17344227
2012 PHD12 and Snail2 independently interact with Sin3A, which complexes with HDAC; this PHD12-Sin3A/HDAC-Snail2 complex is recruited to the Cad6b promoter, deacetylates histone H3 lysines, and thereby represses Cad6b to drive neural crest EMT in chick embryos. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), histone acetylation assays, morpholino knockdown of PHD12 and Snail2 Journal of Cell Biology High 22986495
2015 Snail2/Slug cooperates with EZH2 (catalytic subunit of PRC2) to regulate neural crest development; EZH2 directly interacts with Snail2, and Snail2 modulates EZH2 occupancy and H3K27 trimethylation at the E-cadherin promoter. Co-immunoprecipitation, chromatin immunoprecipitation, Ezh2 knockdown in Xenopus, neural crest marker/migration assays Development High 25617436
2013 Snail2 requires intact ZF3 or ZF4 (but not ZF1/ZF2) for efficient E-cadherin E2-box binding and EMT induction, demonstrating non-equivalent roles of individual zinc fingers compared with Snail1; differential E2-box distribution in mouse vs. human E-cadherin promoters also contributes to differential activity. Protein–DNA modeling, zinc-finger point mutants, luciferase reporter assays, EMT functional assays Journal of Biological Chemistry High 24297167
2012 Both the N-terminal SNAG domain and the central SLUG domain of Snail2 are required for efficient E-cadherin promoter repression; NCoR co-repressor interacts with Snail2 through the SNAG domain, and CtBP1 is recruited through the SLUG domain. Phosphorylation at serine 4 modulates Snail2 repressor activity and EMT induction. Domain deletion/mutation analysis, co-immunoprecipitation, luciferase reporter assays, in vivo phosphorylation site identification (mass spectrometry), functional EMT assays PLoS One High 22567133
2004 Snail and Slug directly repress transcription of multiple proapoptotic factors, conferring resistance to DNA damage–induced programmed cell death; RNAi depletion of endogenous Snail increased apoptotic sensitivity and elevated expression of the identified proapoptotic targets. Exogenous expression in cancer cells, RNAi knockdown, molecular analysis of proapoptotic target gene expression, DNA-damage survival assays Molecular and Cellular Biology Medium 15314165
2008 Ligand-activated ERα suppresses Slug transcription by forming a co-repressor complex of ERα, HDAC1, and N-CoR that binds three half-site estrogen response elements (EREs) in the Slug promoter; ERα also indirectly represses Slug via PI3K/Akt-mediated GSK-3β inactivation. ERα transfection/knockdown in breast cancer cells, chromatin immunoprecipitation (sequential ChIP confirming ternary complex), luciferase reporter assays, pharmacological inhibition Biochemical Journal / Oncogene High 18588516 20101232
2012 GSK-3β phosphorylates Slug/Snail2 at serine residues S92/96 and S100/104; S92/96 phosphorylation promotes degradation, while S100/104 phosphorylation controls nuclear localization. Mutation of these sites enhances EMT properties relative to wild-type Slug. Site-directed mutagenesis of GSK-3β phosphorylation sites, cycloheximide chase assays for protein stability, nuclear/cytoplasmic fractionation, EMT marker assays FEBS Journal Medium 22727060
2019 USP5 deubiquitinase interacts with SLUG and stabilizes it by removing ubiquitin chains; USP5 knockdown inhibits SLUG deubiquitination and promotes its proteasomal degradation, whereas USP5 overexpression increases SLUG stability and enhances EMT and invasion of hepatocellular carcinoma cells. Affinity purification, mass spectrometry, co-immunoprecipitation, cycloheximide chase assays, deubiquitination assays, dual-luciferase/ChIP assays for SLUG-E-cadherin axis, SPR binding Theranostics High 30809294
2020 USP20 deubiquitinase stabilizes SNAI2/SLUG by regulating its ubiquitination; identified through comprehensive DUB gain- and loss-of-function screens using cDNA and siRNA libraries, and shown to promote breast cancer migration, invasion, and metastasis. DUB cDNA library gain-of-function screen (65 genes), siRNA library loss-of-function screen (98 genes), ubiquitination assays, migration/invasion assays, in vivo metastasis models Genes & Development High 32943575
2018 USP10 deubiquitinase interacts with Slug and mediates its proteasomal degradation by removing ubiquitin; USP10 knockdown suppresses Slug levels and cell migration, while USP10 overexpression elevates Slug and vimentin levels. Genome-wide siRNA DUB screen, co-immunoprecipitation, proteasome inhibitor assays, cell migration assays Biochemical and Biophysical Research Communications Medium 29803676
2023 FBXO28, an F-box protein (SCF E3 ubiquitin ligase substrate receptor), directly binds SNAI2 and targets it for ubiquitin–proteasome degradation in a PKA-cooperative manner; FBXO28 loss promotes EMT and metastasis of hepatocellular carcinoma. Direct binding assay (Co-IP), ubiquitination assays, in vitro and in vivo metastasis models, correlation in clinical HCC specimens Oncogene Medium 37596321
2014 p14ARF/p19Arf stabilizes SLUG through increased SUMOylation at lysine 192; ARF inactivation reduces Slug levels leading to increased E-cadherin, and this Arf/Slug/E-cadherin axis promotes prostate tumorigenesis in vivo. Mouse genetic models (Pten/Trp53/p19Arf null), biochemical analysis of SUMOylation at K192 by site-directed mutagenesis, western blotting, in vivo tumor progression assays Molecular Oncology Medium 24910389
2019 Hypoxia promotes Slug SUMOylation at residues within amino acids 130–212 (Ubc9 binding) and 33–129 (PIASy binding); SUMOylation enhances Slug transcriptional repression by recruiting more HDAC1, resulting in increased target gene silencing and lung cancer metastasis. Hypoxia increases Slug SUMOylation by attenuating Slug interactions with SENP1 and SENP2. Yeast two-hybrid screening (identifying Ubc9 and SUMO-1), in vitro SUMOylation assays, co-immunoprecipitation, EMSA, reporter assay, ChIP assay, tail-vein metastasis model Journal of Experimental & Clinical Cancer Research High 30612578
2020 CBP acetyltransferase directly interacts with the C-terminal domain of Slug through its HAT domain and acetylates Slug at lysines 166 and 211; this acetylation doubles Slug half-life, increases its stability, promotes E-cadherin downregulation, and enhances breast cancer cell migration. Co-immunoprecipitation of CBP-Slug complex, in vitro acetyltransferase assay, acetylation-specific antibodies, cycloheximide chase (half-life measurement), EMT marker and migration assays Science China Life Sciences Medium 32737855
2015 Vimentin acts as a scaffold to recruit Slug to ERK, promoting ERK-mediated phosphorylation of Slug at serine-87; site-directed mutagenesis of S87 established a requirement for this phosphorylation in EMT initiation. Vimentin-ERK interaction also promotes ERK activation and enhanced vimentin transcription in a feedback loop. RNAi ablation, biochemical co-immunoprecipitation, site-directed mutagenesis (Slug S87), cancer cell migration/invasion assays, subcellular co-localization in clinical specimens Cancer Research High 25855378
2014 Slug directly represses Puma (Bbc3) transcription; N-cadherin induces Slug, which suppresses Puma-mediated apoptosis to promote tumor cell survival at metastatic sites. Inhibition of Puma by RNAi in Slug-knockdown cells rescued lung colonization, confirming the Slug-Puma axis. shRNA knockdown, genetic rescue (Puma RNAi in Slug-KD cells), lung colonization assays in vivo (PyMT model), caspase/PARP cleavage assays, confirmed in human breast cancer cells Cancer Research High 24830722
2019 G9a and histone deacetylases (HDACs) interact with Snail2 to form a repressor complex at the E-cadherin promoter; this complex increases H3K9 methylation and decreases H3K4 and H3K56 acetylation to suppress E-cadherin transcription. G9a and HDAC inhibition significantly reverses Snail2-promoted migration/invasion. Co-immunoprecipitation (Snail2-G9a-HDAC complex), chromatin immunoprecipitation (histone modifications at E-cadherin promoter), pharmacological inhibition, in vitro and in vivo metastasis assays Cancer Science High 31432592
2018 Snail2 interacts with HDAC6 and recruits HDAC6 and PRC2 to the E-cadherin promoter, epigenetically suppressing E-cadherin expression to promote EMT and colorectal cancer metastasis. Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, in vitro and in vivo metastasis models Clinical Epigenetics Medium 30541610
2009 Snail2/Slug (but not Zeb1, Zeb2, E47, or Twist1) directly represses the vitamin D receptor (VDR) gene promoter; Snail2 and Snail1 show additive repression of VDR, and Snail2 blocks 1,25(OH)2D3-induced E-cadherin induction and downstream VDR target gene activation. Luciferase reporter assays for VDR promoter, RT-PCR/western blot for VDR and target genes, comparison of EMT-inducing transcription factors Carcinogenesis Medium 19502595
2011 Twist1 directly binds an evolutionarily conserved E-box on the Snail2 promoter to induce its transcription; Snail2 induction is essential for Twist1-mediated E-cadherin repression, cell invasion, and distant metastasis in mice. ChIP (Twist1 binding to Snail2 promoter E-box), Snail2 knockdown in Twist1-expressing cells, in vivo metastasis assays, E-cadherin promoter repression assays Cancer Research High 21199805
2014 SNAI2 directly binds E-box sites in the PTEN promoter and represses PTEN transcription; SLUG overexpression decreases PTEN at protein and RNA levels, SLUG knockdown increases PTEN, and PTEN knockdown rescues drug resistance in SLUG-depleted prostate cancer cells. Luciferase reporter assay (PTEN promoter), ChIP (SLUG binding to PTEN promoter E-boxes), western blot/qPCR, shRNA rescue experiments The Prostate Medium 25728608
2014 SNAI2 represses the miR-145 promoter activity, thereby decreasing miR-145 expression and reducing 5-fluorouracil sensitivity in colorectal cancer; miR-145 replacement restores 5-FU sensitivity. miR-145 luciferase promoter assay, stable SNAI2 overexpression, shRNA knockdown, 5-FU sensitivity assays Molecular Cancer Therapeutics Medium 25249558
2008 EGF receptor activates Erk5, which in turn induces Slug mRNA expression in keratinocytes; Erk5 pathway inhibition completely blocked keratinocyte migration and Slug induction, while Erk5 shRNA decreased motility and disrupted desmosome organization. EGF treatment with Erk5 pathway inhibitors, shRNA knockdown of Erk5, ectopic Erk5 activation, wound-healing assays, morphological analysis Molecular Biology of the Cell Medium 18716062
2006 Slug binds to an E-box sequence in the integrin α3 promoter and represses α3 transcription in keratinocytes; Slug activation also down-regulates E-cadherin and integrins β1 and β4, reducing cell adhesion to fibronectin and laminin-5. Slug overexpression, ChIP/EMSA (Slug binding to α3 promoter E-box), promoter luciferase reporter, cell adhesion assays Journal of Biological Chemistry Medium 16707493
2014 SNAI2 levels are regulated during cell cycle progression: cyclin E–CDK2 phosphorylates Slug at Ser-54 and Ser-104 at G1/S transition, causing its ubiquitylation and degradation. Non-phosphorylatable Slug is stabilized, downregulates DNA synthesis and checkpoint proteins (TOP1, DNA Ligase IV, Rad17), reduces proliferation, delays S-phase progression, and contributes to genome instability. Cell cycle synchronization, site-directed mutagenesis of Ser-54/Ser-104, cyclin E co-expression, ubiquitylation assays, cell cycle analysis (flow cytometry), genome stability assays Oncogene High 24662826
2019 SNAI1 binds two E-box sequences in the SNAI2 promoter and recruits HDAC1 and HDAC2, causing histone H3 deacetylation and transcriptional repression of SNAI2; HDAC inhibition partially rescues SNAI2 expression in SNAI1-overexpressing cells. ChIP (SNAI1 binding to SNAI2 promoter E-boxes, HDAC1/2 enrichment), epigenetic inhibitor treatments, promoter deletion analysis, histone acetylation assays Scientific Reports Medium 31165775
2012 Slug and Sox9 act cooperatively to determine the mammary stem cell (MaSC) state; inhibition of either blocks MaSC activity, and transient co-expression of exogenous Slug and Sox9 converts differentiated luminal cells into MaSCs with long-term mammary gland-reconstituting ability. Slug and Sox9 induce MaSCs by activating distinct autoregulatory gene expression programs. shRNA inhibition in primary mammary epithelial cells, transient co-expression/conversion assays, mammary gland transplantation (long-term reconstitution), gene expression profiling Cell High 22385965
2019 Slug facilitates efficient RPA32-mediated DNA damage response (DDR) signaling; Slug deficiency delays phosphorylation of ATR and its effectors RPA32 and CHK1, impairs RAD51 recruitment to DNA damage sites, and leads to persistence of unresolved DNA damage and premature aging of mammary epithelium in vivo. Slug/Snai2 knockout mice (in vivo), phosphorylation analysis of ATR/RPA32/CHK1, RAD51 recruitment foci assays, DDR signaling analysis in primary mammary epithelial cells Cell Reports Medium 31291576
2014 Slug controls the differentiation status of epidermal progenitor cells by binding to and repressing differentiation gene promoters; loss of SNAI2 causes premature differentiation, while gain of SNAI2 inhibits differentiation. SNAI2 is enriched in the basal progenitor layer and extinguished upon differentiation. SNAI2 knockdown and overexpression in human epidermal keratinocytes, ChIP (SNAI2 binding to differentiation gene targets), differentiation marker assays, in vivo epidermal analysis Stem Cells Medium 25100569
2020 Slug in angiogenic endothelial cells suppresses Dll4-Notch signaling, thereby promoting VEGFR2 expression. EC-specific Slug re-expression and reduced Notch signaling (via γ-secretase inhibition or Dll4 loss) rescue retinal angiogenesis in SlugKO mice; Slug is activated by SDF1α via CXCR4 and the MAP kinase ERK5. Slug knockout mice, EC-specific re-expression, γ-secretase inhibition, Dll4 genetic loss, retinal angiogenesis assays, VEGF signaling inhibition, pharmacological CXCR4/ERK5 pathway analysis Nature Communications High 33106502
2014 Slug regulates MT1-MMP expression in endothelial cells; siRNA knockdown of Slug inhibits sprouting and migration in angiogenesis assays, and re-expression of MT1-MMP rescues the sprouting defect caused by Slug loss. MMP2 and MMP9 activity is also affected by Slug, likely through MT1-MMP. siRNA knockdown, lentiviral MT1-MMP re-expression rescue, in vitro angiogenesis assays, MMP activity assays Journal of Cell Science Medium 24554431
2021 SNAI2 is transcriptionally activated by MYOD via super enhancers with striped 3D contact architecture; SNAI2 protein then binds enhancer elements and competes with MYOD at a subset of myogenic enhancers, suppressing terminal muscle differentiation. RAS/MEK signaling modulates SNAI2 levels and chromatin binding. ChIP-seq (genome-wide chromatin binding), super enhancer analysis, 3D chromatin architecture (Hi-C), SNAI2 knockdown/overexpression, differentiation assays Nature Communications High 33420019
2016 LOX (lysyl oxidase) directly binds and transactivates the SNAI2 promoter; LOX knockdown reduces SNAI2 expression in vitro and in a metastatic thyroid cancer mouse model. LOX/SNAI2 axis reduces TIMP4 secretion. LOX nuclear entry and SNAI2 promoter binding was demonstrated by ChIP and luciferase reporter assays. ChIP assay, promoter luciferase assay, LOX knockdown in vitro and in vivo (mouse metastasis model), protein array for MMPs/TIMPs Clinical Cancer Research Medium 27029493
2022 SNAI2 directly binds to the SLC7A11 promoter and activates its transcription, thereby inhibiting ferroptosis in ovarian cancer cells; SNAI2 knockdown promotes ferroptosis (similar to erastin treatment) and suppresses tumor growth. Luciferase reporter assay, chromatin immunoprecipitation (SNAI2 binding to SLC7A11 promoter), RNAi knockdown, ferroptosis assays, xenograft mouse model Bioengineered Medium 35220872
2022 SNAI2 is transcriptionally activated by FOXO3 upon energy stress and interacts directly with FOXO3 to form a feed-forward regulatory loop reinforcing expression of autophagy genes; SNAI2 binding to FOXO3 abrogates CRM1-dependent FOXO3 nuclear export, thus retaining FOXO3 in the nucleus. A dFoxO-Snail feed-forward loop also regulates autophagy in Drosophila. Genome-wide screen in HeLa cells, co-immunoprecipitation (SNAI2-FOXO3 interaction), nuclear export assays (CRM1 inhibition), autophagy assays, Drosophila genetic validation PNAS High 35271390
2002 MITF transactivates the SLUG promoter; and Slugh and Kit genetically interact in vivo. Homozygous deletions in SLUG in Waardenburg syndrome type 2 patients result in absence of SLUG protein and neural crest-derived cell lineage defects (auditory-pigmentary symptoms). Human patient genetics (homozygous SLUG deletions), promoter transactivation assay (MITF on SLUG promoter), in vivo genetic interaction analysis (Slugh × Kit) Human Molecular Genetics Medium 12444107
2011 In Xenopus, Snail2 is required in the C2/C3 lateral mesoderm lineage for mesodermal induction of neural crest; loss of snail2 function blocks neural crest but not mesoderm formation in this lineage, and can be synergistically rescued by bmp4 and wnt8 RNAs, indicating Snail2 regulates BMP and Wnt agonist/antagonist expression levels for mesodermal neural crest induction. Targeted blastomere injection, morpholino-based loss of function, explant assays, BMP4/Wnt8 RNA rescue Development Medium 21715424
2018 Slug binds to the E-box of the type I collagen (COL1A1) promoter in buccal mucosal fibroblasts, leading to increased type I collagen expression and myofibroblast transdifferentiation (arecoline-induced fibrogenesis); Slug silencing prevents arecoline-induced myofibroblast activation. ChIP (Slug binding to COL1A1 E-box), Slug knockdown/overexpression in fibroblasts, arecoline treatment, myofibroblast activity assays Journal of Cellular Physiology Medium 30230545
2019 HNF1B transcriptionally represses SLUG expression through interaction with RBBP7/RbAP46; EZH2 suppresses HNF1B expression by binding its locus, thereby relieving repression of SLUG and promoting EMT in prostate cancer. HNF1B binds SLUG promoter targets. ChIP (EZH2 at HNF1B locus), co-immunoprecipitation (HNF1B-RBBP7 interaction), gene expression rescue experiments, genome-wide target binding analysis Oncogene Medium 31636385

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 818 22385965
2011 Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer research 333 21199805
2004 Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Molecular and cellular biology 279 15314165
2011 The EMT regulator slug and lung carcinogenesis. Carcinogenesis 272 21665887
1998 The Slug gene is not essential for mesoderm or neural crest development in mice. Developmental biology 201 9659933
2002 SLUG (SNAI2) deletions in patients with Waardenburg disease. Human molecular genetics 174 12444107
2012 The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PloS one 172 22911700
2007 Snail2 directly represses cadherin6B during epithelial-to-mesenchymal transitions of the neural crest. Development (Cambridge, England) 161 17344227
2010 ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene 155 20101232
2007 Function of the zinc-finger transcription factor SNAI2 in cancer and development. Annual review of genetics 153 17550342
2020 Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer. The Journal of experimental medicine 151 32510550
2010 SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC cancer 149 20691079
2008 Erk5 controls Slug expression and keratinocyte activation during wound healing. Molecular biology of the cell 135 18716062
2013 Differential role of Snail1 and Snail2 zinc fingers in E-cadherin repression and epithelial to mesenchymal transition. The Journal of biological chemistry 133 24297167
2010 SNAI2/Slug promotes growth and invasion in human gliomas. BMC cancer 132 20565806
2019 USP5 promotes epithelial-mesenchymal transition by stabilizing SLUG in hepatocellular carcinoma. Theranostics 117 30809294
2014 SLUG: Critical regulator of epithelial cell identity in breast development and cancer. Cell adhesion & migration 116 25482617
2015 Vimentin-ERK Signaling Uncouples Slug Gene Regulatory Function. Cancer research 115 25855378
2014 Angiogenic sprouting is regulated by endothelial cell expression of Slug. Journal of cell science 95 24554431
2009 Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis 95 19502595
2005 SLUG in cancer development. Oncogene 93 15735690
2020 Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis. Nature communications 87 33106502
2017 MiR-122 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Snail1 and Snail2 and suppressing WNT/β-cadherin signaling pathway. Experimental cell research 87 28890291
2010 Expression of transcription factors snail, slug, and twist in human bladder carcinoma. Journal of experimental & clinical cancer research : CR 87 20809941
2013 Angiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motility. The Journal of clinical investigation 85 23434592
2015 The transcription factors Slug (SNAI2) and Snail (SNAI1) regulate phospholipase D (PLD) promoter in opposite ways towards cancer cell invasion. Molecular oncology 84 26781944
2019 Molecular regulation of Snai2 in development and disease. Journal of cell science 83 31792043
2020 Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2. Genes & development 80 32943575
2017 Long non-coding RNA UCA1 regulates the expression of Snail2 by miR-203 to promote hepatocellular carcinoma progression. Journal of cancer research and clinical oncology 79 28271214
2006 Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes. The Journal of biological chemistry 79 16707493
2012 Expression of epithelial-mesenchymal transition regulators SNAI2 and TWIST1 in thyroid carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 76 22899291
2010 Slug/SNAI2 regulates cell proliferation and invasiveness of metastatic prostate cancer cell lines. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 76 20506051
2012 Functional regulation of Slug/Snail2 is dependent on GSK-3β-mediated phosphorylation. The FEBS journal 68 22727060
2014 hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness. Oncogene 66 25151968
2008 Slug (SNAI2) down-regulation by RNA interference facilitates apoptosis and inhibits invasive growth in neuroblastoma preclinical models. Clinical cancer research : an official journal of the American Association for Cancer Research 64 18628477
2015 Expression of EMT Markers SLUG and TWIST in Breast Cancer. Anticancer research 62 26124343
2012 Slug expression during melanoma progression. The American journal of pathology 61 22503751
2012 A PHD12-Snail2 repressive complex epigenetically mediates neural crest epithelial-to-mesenchymal transition. The Journal of cell biology 61 22986495
2011 Snail1, Snail2, and E47 promote mammary epithelial branching morphogenesis. The EMBO journal 61 21610693
2015 Snail2/Slug cooperates with Polycomb repressive complex 2 (PRC2) to regulate neural crest development. Development (Cambridge, England) 60 25617436
2014 SNAI2 controls the undifferentiated state of human epidermal progenitor cells. Stem cells (Dayton, Ohio) 59 25100569
2016 Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 58 27029493
2008 ERalpha suppresses slug expression directly by transcriptional repression. The Biochemical journal 56 18588516
2014 Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis. Molecular oncology 55 24910389
2019 G9a and histone deacetylases are crucial for Snail2-mediated E-cadherin repression and metastasis in hepatocellular carcinoma. Cancer science 51 31432592
2018 Reciprocal expression of Slug and Snail in human oral cancer cells. PloS one 51 29969465
2014 SNAI2 modulates colorectal cancer 5-fluorouracil sensitivity through miR145 repression. Molecular cancer therapeutics 51 25249558
2012 Characterization of the SNAG and SLUG domains of Snail2 in the repression of E-cadherin and EMT induction: modulation by serine 4 phosphorylation. PloS one 50 22567133
2018 Epigenetic suppression of E-cadherin expression by Snail2 during the metastasis of colorectal cancer. Clinical epigenetics 49 30541610
2016 ΔNp63α induces the expression of FAT2 and Slug to promote tumor invasion. Oncotarget 48 27081041
2020 SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET. Oncogene 46 32111984
2020 Slug and E-Cadherin: Stealth Accomplices? Frontiers in molecular biosciences 44 32760736
2013 Compensatory regulation of the Snai1 and Snai2 genes during chondrogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 44 23322385
2014 Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis. Cancer research 42 24830722
2022 SNAI2 promotes the development of ovarian cancer through regulating ferroptosis. Bioengineered 41 35220872
2019 Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis. Journal of experimental & clinical cancer research : CR 41 30612578
2019 HNF1B-mediated repression of SLUG is suppressed by EZH2 in aggressive prostate cancer. Oncogene 41 31636385
2011 Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility. Cell adhesion & migration 41 21785273
1998 Human SLUG gene organization, expression, and chromosome map location on 8q. Genomics 40 9721220
2021 Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma. Nature communications 39 33420019
2016 Slug Is Associated With Tumor Metastasis and Angiogenesis in Ovarian Cancer. Reproductive sciences (Thousand Oaks, Calif.) 39 27368877
2011 Snail2 controls mesodermal BMP/Wnt induction of neural crest. Development (Cambridge, England) 39 21715424
2010 The transcription factors Snail1 and Snail2 repress vitamin D receptor during colon cancer progression. The Journal of steroid biochemistry and molecular biology 39 20138990
2009 Unexpected functional redundancy between Twist and Slug (Snail2) and their feedback regulation of NF-kappaB via Nodal and Cerberus. Developmental biology 39 19389392
2008 A Myc-Slug (Snail2)/Twist regulatory circuit directs vascular development. Development (Cambridge, England) 39 18469221
2019 Loss of Slug Compromises DNA Damage Repair and Accelerates Stem Cell Aging in Mammary Epithelium. Cell reports 38 31291576
2015 SLUG is a direct transcriptional repressor of PTEN tumor suppressor. The Prostate 38 25728608
2023 EGR1 induces EMT in pancreatic cancer via a P300/SNAI2 pathway. Journal of translational medicine 37 36932397
2019 SNAI1 recruits HDAC1 to suppress SNAI2 transcription during epithelial to mesenchymal transition. Scientific reports 37 31165775
2018 USP10 regulates the stability of the EMT-transcription factor Slug/SNAI2. Biochemical and biophysical research communications 36 29803676
2016 RCP induces Slug expression and cancer cell invasion by stabilizing β1 integrin. Oncogene 36 27524413
2020 CBP-mediated Slug acetylation stabilizes Slug and promotes EMT and migration of breast cancer cells. Science China. Life sciences 35 32737855
2019 Sphingosine 1-phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30844311
2018 Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa. Journal of cellular physiology 33 30230545
2014 Pro-chondrogenic effect of miR-221 and slug depletion in human MSCs. Stem cell reviews and reports 33 24923882
2014 Slug is temporally regulated by cyclin E in cell cycle and controls genome stability. Oncogene 32 24662826
2014 Slug promotes hepatocellular cancer cell progression by increasing sox2 and nanog expression. Oncology reports 32 25339068
2021 SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2. Cancer science 30 34628696
2019 C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake. Oncogene 29 31562393
2015 SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer. Cancer microenvironment : official journal of the International Cancer Microenvironment Society 28 26412079
2011 Expression of Snail2 in long bone osteosarcomas correlates with tumour malignancy. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 27 21207222
2003 Slug expression during organogenesis in mice. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 27 12552634
1997 Chemotaxis to cAMP and slug migration in Dictyostelium both depend on migA, a BTB protein. Molecular biology of the cell 27 9307972
2020 DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics 26 32754286
2022 EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling. Cellular signalling 25 35085771
2016 miR-124 modulates gefitinib resistance through SNAI2 and STAT3 in non-small cell lung cancer. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 24 27924500
2016 MicroRNA-124 inhibits cell proliferation and migration by regulating SNAI2 in breast cancer. Oncology reports 23 27748910
2013 Snail2 promotes osteosarcoma cell motility through remodelling of the actin cytoskeleton and regulates tumor development. Cancer letters 23 23352643
2022 CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug. Molecular cancer 22 36536414
2021 FOXD1 promotes EMT and cell stemness of oral squamous cell carcinoma by transcriptional activation of SNAI2. Cell & bioscience 22 34348789
2021 Bile acids increase intestinal marker expression via the FXR/SNAI2/miR-1 axis in the stomach. Cellular oncology (Dordrecht, Netherlands) 22 34510400
2017 Snail2 and Zeb2 repress P-cadherin to define embryonic territories in the chick embryo. Development (Cambridge, England) 22 28087626
2023 FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation. Oncogene 21 37596321
2022 A coherent FOXO3-SNAI2 feed-forward loop in autophagy. Proceedings of the National Academy of Sciences of the United States of America 21 35271390
2007 Snai2 expression enhances ultraviolet radiation-induced skin carcinogenesis. The American journal of pathology 21 17916597
2004 Expression of chicken slug and snail in mesenchymal components of the developing central nervous system. Developmental dynamics : an official publication of the American Association of Anatomists 21 15108319
2021 KLF4, Slug and EMT in Head and Neck Squamous Cell Carcinoma. Cells 20 33802627
2020 Histone Deacetylases Inhibit the Snail2-Mediated EMT During Metastasis of Hepatocellular Carcinoma Cells. Frontiers in cell and developmental biology 20 32850856
2017 MicroRNA-124 inhibits cell invasion and epithelial-mesenchymal transition by directly repressing Snail2 in gastric cancer. European review for medical and pharmacological sciences 20 28829503
2016 TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program. Journal of molecular cell biology 20 27651430

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