{"gene":"SNAI2","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"Morpholino knockdown, quantitative PCR, in vivo and in vitro chromatin immunoprecipitation/EMSA on cadherin6B promoter E-boxes","journal":"Development","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — direct binding demonstrated by multiple orthogonal biochemical assays (ChIP, EMSA) combined with in vivo loss-of-function with defined target-gene readout","pmids":["17344227"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), histone acetylation assays, morpholino knockdown of PHD12 and Snail2","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying complex members, ChIP at target promoter, loss-of-function phenotype, multiple orthogonal methods in one study","pmids":["22986495"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, Ezh2 knockdown in Xenopus, neural crest marker/migration assays","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction (Co-IP), ChIP showing H3K27me3 changes at target promoter, in vivo loss-of-function with defined neural crest phenotype","pmids":["25617436"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Protein–DNA modeling, zinc-finger point mutants, luciferase reporter assays, EMT functional assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis of specific DNA-binding residues combined with functional EMT assays, single lab but multiple orthogonal approaches","pmids":["24297167"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Domain deletion/mutation analysis, co-immunoprecipitation, luciferase reporter assays, in vivo phosphorylation site identification (mass spectrometry), functional EMT assays","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of discrete domains, Co-IP of co-repressors, in vivo phospho-site mapping, multiple orthogonal methods in one study","pmids":["22567133"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Exogenous expression in cancer cells, RNAi knockdown, molecular analysis of proapoptotic target gene expression, DNA-damage survival assays","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain- and loss-of-function experiments with defined target-gene readouts, single lab, limited direct promoter-binding data shown in abstract","pmids":["15314165"],"is_preprint":false},{"year":2008,"finding":"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.","method":"ERα transfection/knockdown in breast cancer cells, chromatin immunoprecipitation (sequential ChIP confirming ternary complex), luciferase reporter assays, pharmacological inhibition","journal":"Biochemical Journal / Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — sequential ChIP confirming ERα-HDAC1-NCoR ternary complex at slug promoter EREs, replicated across two publications from same lab (PMID 18588516, 20101232)","pmids":["18588516","20101232"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Site-directed mutagenesis of GSK-3β phosphorylation sites, cycloheximide chase assays for protein stability, nuclear/cytoplasmic fractionation, EMT marker assays","journal":"FEBS Journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis combined with stability and localization assays, single lab, multiple complementary approaches","pmids":["22727060"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Affinity purification, mass spectrometry, co-immunoprecipitation, cycloheximide chase assays, deubiquitination assays, dual-luciferase/ChIP assays for SLUG-E-cadherin axis, SPR binding","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (AP-MS, Co-IP, in vitro deubiquitination, SPR binding, ChIP) in one study establishing the USP5-SLUG stabilization mechanism","pmids":["30809294"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale screen followed by mechanistic validation of ubiquitination regulation, in vitro and in vivo functional assays","pmids":["32943575"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Genome-wide siRNA DUB screen, co-immunoprecipitation, proteasome inhibitor assays, cell migration assays","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genome-wide screen identification confirmed by Co-IP and functional assays, single lab","pmids":["29803676"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Direct binding assay (Co-IP), ubiquitination assays, in vitro and in vivo metastasis models, correlation in clinical HCC specimens","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and ubiquitination mechanistically characterized, in vivo validation, single lab","pmids":["37596321"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Mouse genetic models (Pten/Trp53/p19Arf null), biochemical analysis of SUMOylation at K192 by site-directed mutagenesis, western blotting, in vivo tumor progression assays","journal":"Molecular Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of SUMO site combined with in vivo mouse genetic epistasis, single lab","pmids":["24910389"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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":"Journal of Experimental & Clinical Cancer Research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro SUMOylation reconstitution with mutagenesis, ChIP confirming HDAC1 recruitment, in vivo metastasis validation; multiple orthogonal methods","pmids":["30612578"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation of CBP-Slug complex, in vitro acetyltransferase assay, acetylation-specific antibodies, cycloheximide chase (half-life measurement), EMT marker and migration assays","journal":"Science China Life Sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — biochemical acetyltransferase assay, direct interaction mapped to HAT domain, acetylation sites defined, stability and functional consequences tested; single lab","pmids":["32737855"],"is_preprint":false},{"year":2015,"finding":"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.","method":"RNAi ablation, biochemical co-immunoprecipitation, site-directed mutagenesis (Slug S87), cancer cell migration/invasion assays, subcellular co-localization in clinical specimens","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct protein interactions demonstrated by Co-IP, mutagenesis of phospho-site establishing functional requirement, in vitro and clinical specimen validation; multiple methods in one study","pmids":["25855378"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis rescue experiment (Puma KD rescues Slug KD phenotype), replicated in mouse and human systems, in vivo metastasis model","pmids":["24830722"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation (Snail2-G9a-HDAC complex), chromatin immunoprecipitation (histone modifications at E-cadherin promoter), pharmacological inhibition, in vitro and in vivo metastasis assays","journal":"Cancer Science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP defining complex, ChIP showing histone modification changes, pharmacological rescue, in vivo validation; multiple orthogonal methods in one study","pmids":["31432592"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, in vitro and in vivo metastasis models","journal":"Clinical Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP establishing complex at E-cadherin promoter, in vivo validation; single lab","pmids":["30541610"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Luciferase reporter assays for VDR promoter, RT-PCR/western blot for VDR and target genes, comparison of EMT-inducing transcription factors","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter reporter assays with specificity comparison across multiple EMT-TFs, single lab; direct promoter binding not fully characterized in abstract","pmids":["19502595"],"is_preprint":false},{"year":2011,"finding":"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.","method":"ChIP (Twist1 binding to Snail2 promoter E-box), Snail2 knockdown in Twist1-expressing cells, in vivo metastasis assays, E-cadherin promoter repression assays","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter occupancy, epistasis (Snail2 KD blocks Twist1 EMT), in vivo metastasis validation; multiple orthogonal methods","pmids":["21199805"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Luciferase reporter assay (PTEN promoter), ChIP (SLUG binding to PTEN promoter E-boxes), western blot/qPCR, shRNA rescue experiments","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, epistasis rescue experiment (PTEN KD rescues SLUG KD phenotype); single lab","pmids":["25728608"],"is_preprint":false},{"year":2014,"finding":"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.","method":"miR-145 luciferase promoter assay, stable SNAI2 overexpression, shRNA knockdown, 5-FU sensitivity assays","journal":"Molecular Cancer Therapeutics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct promoter repression by luciferase assay, functional rescue with miR-145 replacement; single lab","pmids":["25249558"],"is_preprint":false},{"year":2008,"finding":"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.","method":"EGF treatment with Erk5 pathway inhibitors, shRNA knockdown of Erk5, ectopic Erk5 activation, wound-healing assays, morphological analysis","journal":"Molecular Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological and genetic (shRNA) perturbation of Erk5 with Slug mRNA and functional readouts, defining EGFR/Erk5/Slug pathway; single lab","pmids":["18716062"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Slug overexpression, ChIP/EMSA (Slug binding to α3 promoter E-box), promoter luciferase reporter, cell adhesion assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP/EMSA confirmed, functional adhesion readout; single lab","pmids":["16707493"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phospho-site mutagenesis with functional cell cycle and ubiquitylation readouts, multiple complementary methods in one study","pmids":["24662826"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP (SNAI1 binding to SNAI2 promoter E-boxes, HDAC1/2 enrichment), epigenetic inhibitor treatments, promoter deletion analysis, histone acetylation assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter occupancy and HDAC1/2 recruitment, pharmacological rescue; single lab","pmids":["31165775"],"is_preprint":false},{"year":2012,"finding":"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.","method":"shRNA inhibition in primary mammary epithelial cells, transient co-expression/conversion assays, mammary gland transplantation (long-term reconstitution), gene expression profiling","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mammary reconstitution as functional gold standard, loss-of-function in primary cells, replicated across multiple experimental approaches","pmids":["22385965"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Slug/Snai2 knockout mice (in vivo), phosphorylation analysis of ATR/RPA32/CHK1, RAD51 recruitment foci assays, DDR signaling analysis in primary mammary epithelial cells","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with mechanistic phosphorylation readouts identifying DDR pathway defects; single lab, mechanism of direct Slug-DDR component interaction not fully biochemically reconstituted from abstract","pmids":["31291576"],"is_preprint":false},{"year":2014,"finding":"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.","method":"SNAI2 knockdown and overexpression in human epidermal keratinocytes, ChIP (SNAI2 binding to differentiation gene targets), differentiation marker assays, in vivo epidermal analysis","journal":"Stem Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming genome-wide binding to differentiation gene targets, functional differentiation assays with gain and loss of function; single lab","pmids":["25100569"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Slug knockout mice, EC-specific re-expression, γ-secretase inhibition, Dll4 genetic loss, retinal angiogenesis assays, VEGF signaling inhibition, pharmacological CXCR4/ERK5 pathway analysis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple complementary interventions (KO, re-expression, Notch/VEGF pathway manipulation) in vivo, multiple orthogonal approaches identifying Dll4-Notch-VEGFR2 axis","pmids":["33106502"],"is_preprint":false},{"year":2014,"finding":"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.","method":"siRNA knockdown, lentiviral MT1-MMP re-expression rescue, in vitro angiogenesis assays, MMP activity assays","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA knockdown with defined molecular target (MT1-MMP), genetic rescue confirming epistasis; single lab","pmids":["24554431"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ChIP-seq (genome-wide chromatin binding), super enhancer analysis, 3D chromatin architecture (Hi-C), SNAI2 knockdown/overexpression, differentiation assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq defining genome-wide binding and competition with MYOD at enhancers, 3D chromatin architecture, functional differentiation assays; multiple high-quality genomic methods","pmids":["33420019"],"is_preprint":false},{"year":2016,"finding":"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.","method":"ChIP assay, promoter luciferase assay, LOX knockdown in vitro and in vivo (mouse metastasis model), protein array for MMPs/TIMPs","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter luciferase demonstrating direct transactivation, in vivo mouse model validation; single lab","pmids":["27029493"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Luciferase reporter assay, chromatin immunoprecipitation (SNAI2 binding to SLC7A11 promoter), RNAi knockdown, ferroptosis assays, xenograft mouse model","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter confirming direct transactivation of SLC7A11, functional ferroptosis and in vivo assays; single lab","pmids":["35220872"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Genome-wide screen in HeLa cells, co-immunoprecipitation (SNAI2-FOXO3 interaction), nuclear export assays (CRM1 inhibition), autophagy assays, Drosophila genetic validation","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen, Co-IP identifying protein-protein interaction, mechanistic nuclear export assay, replicated in Drosophila demonstrating evolutionary conservation","pmids":["35271390"],"is_preprint":false},{"year":2002,"finding":"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).","method":"Human patient genetics (homozygous SLUG deletions), promoter transactivation assay (MITF on SLUG promoter), in vivo genetic interaction analysis (Slugh × Kit)","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — human genetics with functional promoter assay and in vivo genetic interaction; single study","pmids":["12444107"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Targeted blastomere injection, morpholino-based loss of function, explant assays, BMP4/Wnt8 RNA rescue","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted loss-of-function with lineage-specific epistasis and rescue; Xenopus model, single lab","pmids":["21715424"],"is_preprint":false},{"year":2018,"finding":"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.","method":"ChIP (Slug binding to COL1A1 E-box), Slug knockdown/overexpression in fibroblasts, arecoline treatment, myofibroblast activity assays","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct binding to collagen promoter E-box, functional knockdown confirming role in fibrogenesis; single lab","pmids":["30230545"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP (EZH2 at HNF1B locus), co-immunoprecipitation (HNF1B-RBBP7 interaction), gene expression rescue experiments, genome-wide target binding analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP establishing EZH2-HNF1B-SLUG regulatory axis, genome-wide binding analysis; single lab","pmids":["31636385"],"is_preprint":false}],"current_model":"SNAI2/Slug is a C2H2 zinc-finger transcriptional repressor (ZF3/4 required for E-box binding) that assembles context-dependent co-repressor complexes (NCoR via SNAG domain, CtBP1 via SLUG domain, Sin3A/HDAC, G9a, HDAC6/PRC2) to epigenetically silence target genes including E-cadherin, cadherin6B, P-cadherin, VDR, Puma, PTEN, and SLC7A11; its activity and stability are regulated by multiple post-translational modifications including GSK-3β– and cyclin E/CDK2–mediated phosphorylation (promoting proteasomal degradation), SUMOylation (enhancing repressor activity via HDAC1 recruitment), CBP-mediated acetylation (stabilizing the protein), and competing deubiquitinases (USP5, USP20 stabilizing; USP10, FBXO28/PKA destabilizing); upstream, Slug is induced by Twist1 (direct promoter binding), ERK5 downstream of EGFR, SDF1α/CXCR4/ERK5 in endothelial cells, and SPARC/PI3K-AKT signaling, while ERα-HDAC1-NCoR and SNAI1-HDAC complexes repress its transcription; functionally, Slug cooperates with Sox9 to define mammary stem cell state, with EZH2/PRC2 in neural crest EMT, and with MYOD enhancers in rhabdomyosarcoma, while also regulating DDR signaling (ATR-RPA32-CHK1 axis), autophagy (FOXO3 feed-forward loop), angiogenesis (Dll4-Notch-VEGFR2 suppression), and cell cycle progression."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12444107"],"confidence":"Medium","gaps":["Molecular mechanism linking SLUG loss to specific lineage defects not resolved","Direct downstream targets in affected lineages not defined"]},{"year":2004,"claim":"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","pmids":["15314165"],"confidence":"Medium","gaps":["Limited direct promoter-binding data for individual proapoptotic targets","Specific target genes only partially defined at this stage"]},{"year":2007,"claim":"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","pmids":["17344227"],"confidence":"High","gaps":["Co-repressor machinery at this locus not yet identified","Generalizability to other targets not tested here"]},{"year":2008,"claim":"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","pmids":["18716062","18588516","20101232"],"confidence":"High","gaps":["Direct kinase substrate relationship between ERK5 and Slug not established","How signaling integrates with degradation machinery unclear"]},{"year":2012,"claim":"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","pmids":["22567133","22986495","22385965"],"confidence":"High","gaps":["Context-dependence of complex choice not fully resolved","Structural basis of co-repressor selection not determined"]},{"year":2013,"claim":"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","pmids":["24297167"],"confidence":"High","gaps":["Genome-wide binding consequences of ZF mutations not mapped","Co-factor recruitment dependence on specific fingers not tested"]},{"year":2014,"claim":"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","pmids":["24662826","24910389","24830722","25728608"],"confidence":"High","gaps":["Interplay between competing PTMs on a single Slug molecule unresolved","E3 ligases mediating phospho-degron-dependent turnover not all identified here"]},{"year":2015,"claim":"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","pmids":["25617436","25855378"],"confidence":"High","gaps":["Whether Slug directly recruits PRC2 or acts indirectly not fully separated","Functional hierarchy among multiple phospho-sites not integrated"]},{"year":2018,"claim":"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","pmids":["30541610","29803676"],"confidence":"Medium","gaps":["Reciprocal validation of USP10-Slug interaction limited","Selectivity of HDAC6/PRC2 recruitment across cell types not established"]},{"year":2019,"claim":"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","pmids":["30809294","31432592","30612578","31291576"],"confidence":"High","gaps":["Direct biochemical interaction of Slug with DDR components not reconstituted","How SUMO and ubiquitin marks are coordinated unresolved"]},{"year":2020,"claim":"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","pmids":["32737855","32943575","33106502"],"confidence":"High","gaps":["Combinatorial logic of acetylation, ubiquitination and SUMOylation not integrated","Direct Slug targets within the Dll4-Notch axis not all mapped"]},{"year":2022,"claim":"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","pmids":["35271390","35220872"],"confidence":"High","gaps":["Whether Slug acts as activator versus repressor at distinct loci mechanistically unresolved","Conditions selecting autophagy versus EMT outputs unclear"]},{"year":2023,"claim":"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","pmids":["37596321"],"confidence":"Medium","gaps":["Degron recognized by FBXO28 not mapped","Mechanism of PKA cooperativity not defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,24,21,34]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,16,19,32,34]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,35]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,16,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,27,29,37,30]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,17,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,25,8,9,10,11,13,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,16,34]}],"complexes":["Sin3A/HDAC co-repressor complex","G9a-HDAC repressor complex","HDAC6-PRC2 repressor complex"],"partners":["EZH2","CTBP1","NCOR1","USP5","USP20","FBXO28","CREBBP","FOXO3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43623","full_name":"Zinc finger protein SNAI2","aliases":["Neural crest transcription factor Slug","Protein snail homolog 2"],"length_aa":268,"mass_kda":30.0,"function":"Transcriptional repressor that modulates both activator-dependent and basal transcription. Involved in the generation and migration of neural crest cells. Plays a role in mediating RAF1-induced transcriptional repression of the TJ protein, occludin (OCLN) and subsequent oncogenic transformation of epithelial cells (By similarity). Represses BRCA2 expression by binding to its E2-box-containing silencer and recruiting CTBP1 and HDAC1 in breast cells. In epidermal keratinocytes, binds to the E-box in ITGA3 promoter and represses its transcription. Involved in the regulation of ITGB1 and ITGB4 expression and cell adhesion and proliferation in epidermal keratinocytes. Binds to E-box2 domain of BSG and activates its expression during TGFB1-induced epithelial-mesenchymal transition (EMT) in hepatocytes. Represses E-Cadherin/CDH1 transcription via E-box elements. Involved in osteoblast maturation. Binds to RUNX2 and SOC9 promoters and may act as a positive and negative transcription regulator, respectively, in osteoblasts. Binds to CXCL12 promoter via E-box regions in mesenchymal stem cells and osteoblasts. Plays an essential role in TWIST1-induced EMT and its ability to promote invasion and metastasis","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43623/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNAI2","classification":"Not Classified","n_dependent_lines":114,"n_total_lines":1208,"dependency_fraction":0.09437086092715231},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNAI2","total_profiled":1310},"omim":[{"mim_id":"618335","title":"LONG INTERGENIC NONCODING RNA 958; LINC00958","url":"https://www.omim.org/entry/618335"},{"mim_id":"612741","title":"SNAIL FAMILY TRANSCRIPTIONAL REPRESSOR 3; SNAI3","url":"https://www.omim.org/entry/612741"},{"mim_id":"610386","title":"BTB/POZ DOMAIN-CONTAINING PROTEIN 7; BTBD7","url":"https://www.omim.org/entry/610386"},{"mim_id":"608748","title":"BONE MORPHOGENETIC PROTEIN 10; BMP10","url":"https://www.omim.org/entry/608748"},{"mim_id":"608160","title":"SRY-BOX 9; SOX9","url":"https://www.omim.org/entry/608160"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNAI2"},"hgnc":{"alias_symbol":["SLUGH1","SNAIL2","SLUGH"],"prev_symbol":["SLUG"]},"alphafold":{"accession":"O43623","domains":[{"cath_id":"3.30.160.60","chopping":"158-236","consensus_level":"medium","plddt":91.028,"start":158,"end":236}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43623","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43623-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43623-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNAI2","jax_strain_url":"https://www.jax.org/strain/search?query=SNAI2"},"sequence":{"accession":"O43623","fasta_url":"https://rest.uniprot.org/uniprotkb/O43623.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43623/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43623"}},"corpus_meta":[{"pmid":"22385965","id":"PMC_22385965","title":"Slug and 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Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/27924500","citation_count":24,"is_preprint":false},{"pmid":"23352643","id":"PMC_23352643","title":"Snail2 promotes osteosarcoma cell motility through remodelling of the actin cytoskeleton and regulates tumor development.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/23352643","citation_count":23,"is_preprint":false},{"pmid":"27748910","id":"PMC_27748910","title":"MicroRNA-124 inhibits cell proliferation and migration by regulating SNAI2 in breast cancer.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27748910","citation_count":23,"is_preprint":false},{"pmid":"28087626","id":"PMC_28087626","title":"Snail2 and Zeb2 repress P-cadherin to define embryonic territories in the chick embryo.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28087626","citation_count":22,"is_preprint":false},{"pmid":"34348789","id":"PMC_34348789","title":"FOXD1 promotes EMT and cell stemness of oral squamous cell carcinoma by transcriptional activation of SNAI2.","date":"2021","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/34348789","citation_count":22,"is_preprint":false},{"pmid":"34510400","id":"PMC_34510400","title":"Bile acids increase intestinal marker expression via the FXR/SNAI2/miR-1 axis in the stomach.","date":"2021","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/34510400","citation_count":22,"is_preprint":false},{"pmid":"36536414","id":"PMC_36536414","title":"CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36536414","citation_count":22,"is_preprint":false},{"pmid":"35271390","id":"PMC_35271390","title":"A coherent FOXO3-SNAI2 feed-forward loop in autophagy.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35271390","citation_count":21,"is_preprint":false},{"pmid":"17916597","id":"PMC_17916597","title":"Snai2 expression enhances ultraviolet radiation-induced skin carcinogenesis.","date":"2007","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17916597","citation_count":21,"is_preprint":false},{"pmid":"37596321","id":"PMC_37596321","title":"FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37596321","citation_count":21,"is_preprint":false},{"pmid":"15108319","id":"PMC_15108319","title":"Expression of chicken slug and snail in mesenchymal components of the developing central nervous system.","date":"2004","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15108319","citation_count":21,"is_preprint":false},{"pmid":"33802627","id":"PMC_33802627","title":"KLF4, Slug and EMT in Head and Neck Squamous Cell Carcinoma.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33802627","citation_count":20,"is_preprint":false},{"pmid":"28829503","id":"PMC_28829503","title":"MicroRNA-124 inhibits cell invasion and epithelial-mesenchymal transition by directly repressing Snail2 in gastric cancer.","date":"2017","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28829503","citation_count":20,"is_preprint":false},{"pmid":"27651430","id":"PMC_27651430","title":"TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program.","date":"2016","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27651430","citation_count":20,"is_preprint":false},{"pmid":"32850856","id":"PMC_32850856","title":"Histone Deacetylases Inhibit the Snail2-Mediated EMT During Metastasis of Hepatocellular Carcinoma Cells.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32850856","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47841,"output_tokens":10345,"usd":0.149349,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20914,"output_tokens":4903,"usd":0.113573,"stage2_stop_reason":"end_turn"},"total_usd":0.262922,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown, quantitative PCR, in vivo and in vitro chromatin immunoprecipitation/EMSA on cadherin6B promoter E-boxes\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — direct binding demonstrated by multiple orthogonal biochemical assays (ChIP, EMSA) combined with in vivo loss-of-function with defined target-gene readout\",\n      \"pmids\": [\"17344227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), histone acetylation assays, morpholino knockdown of PHD12 and Snail2\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying complex members, ChIP at target promoter, loss-of-function phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22986495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, Ezh2 knockdown in Xenopus, neural crest marker/migration assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction (Co-IP), ChIP showing H3K27me3 changes at target promoter, in vivo loss-of-function with defined neural crest phenotype\",\n      \"pmids\": [\"25617436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Protein–DNA modeling, zinc-finger point mutants, luciferase reporter assays, EMT functional assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis of specific DNA-binding residues combined with functional EMT assays, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"24297167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion/mutation analysis, co-immunoprecipitation, luciferase reporter assays, in vivo phosphorylation site identification (mass spectrometry), functional EMT assays\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of discrete domains, Co-IP of co-repressors, in vivo phospho-site mapping, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22567133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Exogenous expression in cancer cells, RNAi knockdown, molecular analysis of proapoptotic target gene expression, DNA-damage survival assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain- and loss-of-function experiments with defined target-gene readouts, single lab, limited direct promoter-binding data shown in abstract\",\n      \"pmids\": [\"15314165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"ERα transfection/knockdown in breast cancer cells, chromatin immunoprecipitation (sequential ChIP confirming ternary complex), luciferase reporter assays, pharmacological inhibition\",\n      \"journal\": \"Biochemical Journal / Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — sequential ChIP confirming ERα-HDAC1-NCoR ternary complex at slug promoter EREs, replicated across two publications from same lab (PMID 18588516, 20101232)\",\n      \"pmids\": [\"18588516\", \"20101232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of GSK-3β phosphorylation sites, cycloheximide chase assays for protein stability, nuclear/cytoplasmic fractionation, EMT marker assays\",\n      \"journal\": \"FEBS Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis combined with stability and localization assays, single lab, multiple complementary approaches\",\n      \"pmids\": [\"22727060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Affinity purification, mass spectrometry, co-immunoprecipitation, cycloheximide chase assays, deubiquitination assays, dual-luciferase/ChIP assays for SLUG-E-cadherin axis, SPR binding\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (AP-MS, Co-IP, in vitro deubiquitination, SPR binding, ChIP) in one study establishing the USP5-SLUG stabilization mechanism\",\n      \"pmids\": [\"30809294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale screen followed by mechanistic validation of ubiquitination regulation, in vitro and in vivo functional assays\",\n      \"pmids\": [\"32943575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide siRNA DUB screen, co-immunoprecipitation, proteasome inhibitor assays, cell migration assays\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genome-wide screen identification confirmed by Co-IP and functional assays, single lab\",\n      \"pmids\": [\"29803676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Direct binding assay (Co-IP), ubiquitination assays, in vitro and in vivo metastasis models, correlation in clinical HCC specimens\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and ubiquitination mechanistically characterized, in vivo validation, single lab\",\n      \"pmids\": [\"37596321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse genetic models (Pten/Trp53/p19Arf null), biochemical analysis of SUMOylation at K192 by site-directed mutagenesis, western blotting, in vivo tumor progression assays\",\n      \"journal\": \"Molecular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of SUMO site combined with in vivo mouse genetic epistasis, single lab\",\n      \"pmids\": [\"24910389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screening (identifying Ubc9 and SUMO-1), in vitro SUMOylation assays, co-immunoprecipitation, EMSA, reporter assay, ChIP assay, tail-vein metastasis model\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro SUMOylation reconstitution with mutagenesis, ChIP confirming HDAC1 recruitment, in vivo metastasis validation; multiple orthogonal methods\",\n      \"pmids\": [\"30612578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of CBP-Slug complex, in vitro acetyltransferase assay, acetylation-specific antibodies, cycloheximide chase (half-life measurement), EMT marker and migration assays\",\n      \"journal\": \"Science China Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical acetyltransferase assay, direct interaction mapped to HAT domain, acetylation sites defined, stability and functional consequences tested; single lab\",\n      \"pmids\": [\"32737855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi ablation, biochemical co-immunoprecipitation, site-directed mutagenesis (Slug S87), cancer cell migration/invasion assays, subcellular co-localization in clinical specimens\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interactions demonstrated by Co-IP, mutagenesis of phospho-site establishing functional requirement, in vitro and clinical specimen validation; multiple methods in one study\",\n      \"pmids\": [\"25855378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis rescue experiment (Puma KD rescues Slug KD phenotype), replicated in mouse and human systems, in vivo metastasis model\",\n      \"pmids\": [\"24830722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (Snail2-G9a-HDAC complex), chromatin immunoprecipitation (histone modifications at E-cadherin promoter), pharmacological inhibition, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining complex, ChIP showing histone modification changes, pharmacological rescue, in vivo validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"31432592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, in vitro and in vivo metastasis models\",\n      \"journal\": \"Clinical Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP establishing complex at E-cadherin promoter, in vivo validation; single lab\",\n      \"pmids\": [\"30541610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assays for VDR promoter, RT-PCR/western blot for VDR and target genes, comparison of EMT-inducing transcription factors\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter reporter assays with specificity comparison across multiple EMT-TFs, single lab; direct promoter binding not fully characterized in abstract\",\n      \"pmids\": [\"19502595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (Twist1 binding to Snail2 promoter E-box), Snail2 knockdown in Twist1-expressing cells, in vivo metastasis assays, E-cadherin promoter repression assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter occupancy, epistasis (Snail2 KD blocks Twist1 EMT), in vivo metastasis validation; multiple orthogonal methods\",\n      \"pmids\": [\"21199805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay (PTEN promoter), ChIP (SLUG binding to PTEN promoter E-boxes), western blot/qPCR, shRNA rescue experiments\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, epistasis rescue experiment (PTEN KD rescues SLUG KD phenotype); single lab\",\n      \"pmids\": [\"25728608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"miR-145 luciferase promoter assay, stable SNAI2 overexpression, shRNA knockdown, 5-FU sensitivity assays\",\n      \"journal\": \"Molecular Cancer Therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct promoter repression by luciferase assay, functional rescue with miR-145 replacement; single lab\",\n      \"pmids\": [\"25249558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"EGF treatment with Erk5 pathway inhibitors, shRNA knockdown of Erk5, ectopic Erk5 activation, wound-healing assays, morphological analysis\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological and genetic (shRNA) perturbation of Erk5 with Slug mRNA and functional readouts, defining EGFR/Erk5/Slug pathway; single lab\",\n      \"pmids\": [\"18716062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Slug overexpression, ChIP/EMSA (Slug binding to α3 promoter E-box), promoter luciferase reporter, cell adhesion assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP/EMSA confirmed, functional adhesion readout; single lab\",\n      \"pmids\": [\"16707493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phospho-site mutagenesis with functional cell cycle and ubiquitylation readouts, multiple complementary methods in one study\",\n      \"pmids\": [\"24662826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (SNAI1 binding to SNAI2 promoter E-boxes, HDAC1/2 enrichment), epigenetic inhibitor treatments, promoter deletion analysis, histone acetylation assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter occupancy and HDAC1/2 recruitment, pharmacological rescue; single lab\",\n      \"pmids\": [\"31165775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA inhibition in primary mammary epithelial cells, transient co-expression/conversion assays, mammary gland transplantation (long-term reconstitution), gene expression profiling\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mammary reconstitution as functional gold standard, loss-of-function in primary cells, replicated across multiple experimental approaches\",\n      \"pmids\": [\"22385965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Slug/Snai2 knockout mice (in vivo), phosphorylation analysis of ATR/RPA32/CHK1, RAD51 recruitment foci assays, DDR signaling analysis in primary mammary epithelial cells\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with mechanistic phosphorylation readouts identifying DDR pathway defects; single lab, mechanism of direct Slug-DDR component interaction not fully biochemically reconstituted from abstract\",\n      \"pmids\": [\"31291576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"SNAI2 knockdown and overexpression in human epidermal keratinocytes, ChIP (SNAI2 binding to differentiation gene targets), differentiation marker assays, in vivo epidermal analysis\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming genome-wide binding to differentiation gene targets, functional differentiation assays with gain and loss of function; single lab\",\n      \"pmids\": [\"25100569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Slug knockout mice, EC-specific re-expression, γ-secretase inhibition, Dll4 genetic loss, retinal angiogenesis assays, VEGF signaling inhibition, pharmacological CXCR4/ERK5 pathway analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple complementary interventions (KO, re-expression, Notch/VEGF pathway manipulation) in vivo, multiple orthogonal approaches identifying Dll4-Notch-VEGFR2 axis\",\n      \"pmids\": [\"33106502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, lentiviral MT1-MMP re-expression rescue, in vitro angiogenesis assays, MMP activity assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA knockdown with defined molecular target (MT1-MMP), genetic rescue confirming epistasis; single lab\",\n      \"pmids\": [\"24554431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq (genome-wide chromatin binding), super enhancer analysis, 3D chromatin architecture (Hi-C), SNAI2 knockdown/overexpression, differentiation assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq defining genome-wide binding and competition with MYOD at enhancers, 3D chromatin architecture, functional differentiation assays; multiple high-quality genomic methods\",\n      \"pmids\": [\"33420019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, promoter luciferase assay, LOX knockdown in vitro and in vivo (mouse metastasis model), protein array for MMPs/TIMPs\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter luciferase demonstrating direct transactivation, in vivo mouse model validation; single lab\",\n      \"pmids\": [\"27029493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (SNAI2 binding to SLC7A11 promoter), RNAi knockdown, ferroptosis assays, xenograft mouse model\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter confirming direct transactivation of SLC7A11, functional ferroptosis and in vivo assays; single lab\",\n      \"pmids\": [\"35220872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide screen in HeLa cells, co-immunoprecipitation (SNAI2-FOXO3 interaction), nuclear export assays (CRM1 inhibition), autophagy assays, Drosophila genetic validation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen, Co-IP identifying protein-protein interaction, mechanistic nuclear export assay, replicated in Drosophila demonstrating evolutionary conservation\",\n      \"pmids\": [\"35271390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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).\",\n      \"method\": \"Human patient genetics (homozygous SLUG deletions), promoter transactivation assay (MITF on SLUG promoter), in vivo genetic interaction analysis (Slugh × Kit)\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — human genetics with functional promoter assay and in vivo genetic interaction; single study\",\n      \"pmids\": [\"12444107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Targeted blastomere injection, morpholino-based loss of function, explant assays, BMP4/Wnt8 RNA rescue\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted loss-of-function with lineage-specific epistasis and rescue; Xenopus model, single lab\",\n      \"pmids\": [\"21715424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (Slug binding to COL1A1 E-box), Slug knockdown/overexpression in fibroblasts, arecoline treatment, myofibroblast activity assays\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct binding to collagen promoter E-box, functional knockdown confirming role in fibrogenesis; single lab\",\n      \"pmids\": [\"30230545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (EZH2 at HNF1B locus), co-immunoprecipitation (HNF1B-RBBP7 interaction), gene expression rescue experiments, genome-wide target binding analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP establishing EZH2-HNF1B-SLUG regulatory axis, genome-wide binding analysis; single lab\",\n      \"pmids\": [\"31636385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNAI2/Slug is a C2H2 zinc-finger transcriptional repressor (ZF3/4 required for E-box binding) that assembles context-dependent co-repressor complexes (NCoR via SNAG domain, CtBP1 via SLUG domain, Sin3A/HDAC, G9a, HDAC6/PRC2) to epigenetically silence target genes including E-cadherin, cadherin6B, P-cadherin, VDR, Puma, PTEN, and SLC7A11; its activity and stability are regulated by multiple post-translational modifications including GSK-3β– and cyclin E/CDK2–mediated phosphorylation (promoting proteasomal degradation), SUMOylation (enhancing repressor activity via HDAC1 recruitment), CBP-mediated acetylation (stabilizing the protein), and competing deubiquitinases (USP5, USP20 stabilizing; USP10, FBXO28/PKA destabilizing); upstream, Slug is induced by Twist1 (direct promoter binding), ERK5 downstream of EGFR, SDF1α/CXCR4/ERK5 in endothelial cells, and SPARC/PI3K-AKT signaling, while ERα-HDAC1-NCoR and SNAI1-HDAC complexes repress its transcription; functionally, Slug cooperates with Sox9 to define mammary stem cell state, with EZH2/PRC2 in neural crest EMT, and with MYOD enhancers in rhabdomyosarcoma, while also regulating DDR signaling (ATR-RPA32-CHK1 axis), autophagy (FOXO3 feed-forward loop), angiogenesis (Dll4-Notch-VEGFR2 suppression), and cell cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3, #4]. 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) [#3, #4]. 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 [#1, #2, #17, #18]. 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 [#16, #19, #21, #34]. 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 [#27, #29, #37]. Slug abundance and activity are tightly tuned by post-translational modifications: GSK-3\\u03b2 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 [#7, #25, #13, #14, #8, #9, #10, #11]. Upstream, Slug is induced by Twist1, EGFR/ERK5, and SDF1\\u03b1/CXCR4 signaling and repressed by ER\\u03b1-HDAC1-NCoR and SNAI1-HDAC complexes [#20, #23, #30, #6, #26]. 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 [#28, #35, #30]. Homozygous SNAI2 deletions cause Waardenburg syndrome type 2 with neural-crest-derived auditory-pigmentary defects [#36].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SNAI2 as a clinically relevant neural-crest gene whose loss causes a defined human syndrome, framing its developmental importance.\",\n      \"evidence\": \"Human genetics of homozygous SLUG deletions plus MITF promoter transactivation and Slugh\\u00d7Kit genetic interaction\",\n      \"pmids\": [\"12444107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking SLUG loss to specific lineage defects not resolved\", \"Direct downstream targets in affected lineages not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed Slug functions as a pro-survival repressor of apoptosis, expanding its role beyond adhesion regulation.\",\n      \"evidence\": \"Gain/loss of function in cancer cells with proapoptotic target readouts and DNA-damage survival assays\",\n      \"pmids\": [\"15314165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited direct promoter-binding data for individual proapoptotic targets\", \"Specific target genes only partially defined at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated direct sequence-specific repression in vivo, defining Slug as a bona fide E-box-binding repressor during neural crest EMT.\",\n      \"evidence\": \"Morpholino knockdown in chick embryos with in vivo/in vitro ChIP and EMSA on cadherin6B E-boxes\",\n      \"pmids\": [\"17344227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor machinery at this locus not yet identified\", \"Generalizability to other targets not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified an upstream signaling input (EGFR/ERK5) and a hormonal repressive circuit (ER\\u03b1-HDAC1-NCoR), placing Slug within receptor and nuclear-receptor signaling networks.\",\n      \"evidence\": \"ERK5 pharmacologic/shRNA perturbation with Slug mRNA and migration readouts; sequential ChIP confirming ER\\u03b1-HDAC1-NCoR ternary complex at Slug promoter EREs\",\n      \"pmids\": [\"18716062\", \"18588516\", \"20101232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrate relationship between ERK5 and Slug not established\", \"How signaling integrates with degradation machinery unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the domain logic of Slug repression and the chromatin complexes it assembles, and identified the mammary stem-cell program it controls.\",\n      \"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\",\n      \"pmids\": [\"22567133\", \"22986495\", \"22385965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependence of complex choice not fully resolved\", \"Structural basis of co-repressor selection not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the DNA-binding grammar of Slug, showing ZF3/ZF4 dependence distinguishes it from Snail1.\",\n      \"evidence\": \"Zinc-finger point mutants, protein-DNA modeling, luciferase and EMT assays on E-cadherin E2-box\",\n      \"pmids\": [\"24297167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding consequences of ZF mutations not mapped\", \"Co-factor recruitment dependence on specific fingers not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established Slug as a node controlled by phospho-degradation cell-cycle coupling and SUMO stabilization, and identified key direct survival/tumor-suppressor targets.\",\n      \"evidence\": \"Cyclin E/CDK2 phospho-site mutagenesis with ubiquitylation and cell-cycle assays; p14ARF/SUMOylation mouse genetics; ChIP/rescue for Puma and PTEN repression\",\n      \"pmids\": [\"24662826\", \"24910389\", \"24830722\", \"25728608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between competing PTMs on a single Slug molecule unresolved\", \"E3 ligases mediating phospho-degron-dependent turnover not all identified here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked Slug to PRC2/EZH2-mediated repressive chromatin in neural crest and identified vimentin-scaffolded ERK phosphorylation as an EMT-initiating event.\",\n      \"evidence\": \"Co-IP and ChIP showing EZH2 interaction and H3K27me3 changes in Xenopus; vimentin-ERK scaffold Co-IP with Slug S87 mutagenesis\",\n      \"pmids\": [\"25617436\", \"25855378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Slug directly recruits PRC2 or acts indirectly not fully separated\", \"Functional hierarchy among multiple phospho-sites not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped additional histone-modifying co-repressors (HDAC6/PRC2) and an antagonistic deubiquitinase (USP10) controlling Slug.\",\n      \"evidence\": \"Co-IP/ChIP for HDAC6-PRC2 at E-cadherin promoter; DUB siRNA screen with Co-IP and proteasome assays for USP10\",\n      \"pmids\": [\"30541610\", \"29803676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of USP10-Slug interaction limited\", \"Selectivity of HDAC6/PRC2 recruitment across cell types not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Consolidated the deubiquitinase axis (USP5 stabilizing), the G9a-HDAC repressor complex, the SUMO-HDAC1 activity-enhancing mechanism, and a DNA damage response role.\",\n      \"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\",\n      \"pmids\": [\"30809294\", \"31432592\", \"30612578\", \"31291576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction of Slug with DDR components not reconstituted\", \"How SUMO and ubiquitin marks are coordinated unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CBP acetylation as a stabilizing PTM, USP20 as a metastasis-promoting deubiquitinase, and defined the endothelial Slug-Dll4-Notch-VEGFR2 angiogenic axis.\",\n      \"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\",\n      \"pmids\": [\"32737855\", \"32943575\", \"33106502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic of acetylation, ubiquitination and SUMOylation not integrated\", \"Direct Slug targets within the Dll4-Notch axis not all mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed conserved noncanonical roles of Slug in autophagy (FOXO3 feed-forward loop via CRM1 export control) and ferroptosis suppression (SLC7A11 activation).\",\n      \"evidence\": \"Genome-wide screen, FOXO3 Co-IP and nuclear-export assays, Drosophila validation; SLC7A11 promoter ChIP/reporter with ferroptosis and xenograft assays\",\n      \"pmids\": [\"35271390\", \"35220872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Slug acts as activator versus repressor at distinct loci mechanistically unresolved\", \"Conditions selecting autophagy versus EMT outputs unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified FBXO28 as a direct SCF E3 substrate receptor degrading Slug in a PKA-cooperative manner, refining the ubiquitin-proteasome control of Slug stability.\",\n      \"evidence\": \"Co-IP binding, ubiquitination assays, HCC metastasis models and clinical correlation\",\n      \"pmids\": [\"37596321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron recognized by FBXO28 not mapped\", \"Mechanism of PKA cooperativity not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 24, 21, 34]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 16, 19, 32, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 16, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 27, 29, 37, 30]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 17, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 25, 8, 9, 10, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 16, 34]}\n    ],\n    \"complexes\": [\n      \"Sin3A/HDAC co-repressor complex\",\n      \"G9a-HDAC repressor complex\",\n      \"HDAC6-PRC2 repressor complex\"\n    ],\n    \"partners\": [\n      \"EZH2\",\n      \"CtBP1\",\n      \"NCOR1\",\n      \"USP5\",\n      \"USP20\",\n      \"FBXO28\",\n      \"CREBBP\",\n      \"FOXO3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}