{"gene":"SNAI1","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2012,"finding":"Snail1 interacts with G9a (a major euchromatin H3K9 methyltransferase) and recruits G9a and DNA methyltransferases to the E-cadherin promoter, leading to H3K9me2 and subsequent DNA methylation-mediated repression of E-cadherin.","method":"Co-immunoprecipitation, ChIP, knockdown assays, in vitro and in vivo EMT models","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, functional knockdown with defined phenotypic readout, replicated across multiple cell lines","pmids":["22406531"],"is_preprint":false},{"year":2013,"finding":"Activation of the collagen I receptor DDR2 stimulates ERK2 activity in a Src-dependent manner; activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation, and increased protein half-life, thereby stabilizing SNAIL1 and promoting breast cancer metastasis.","method":"In vitro kinase assay, phosphorylation site mapping, ubiquitylation assays, Co-IP, in vivo metastasis models","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro phosphorylation, functional rescue experiments, in vivo validation","pmids":["23644467"],"is_preprint":false},{"year":2006,"finding":"Snail1 protein binds to an E-box at −146 bp in its own promoter and represses its transcriptional activity, forming a negative feedback regulatory loop that limits Snail1 expression levels.","method":"Chromatin immunoprecipitation (ChIP), promoter-reporter assays, E-box mutagenesis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP with endogenous and ectopic protein, reporter assay, mutagenesis in single lab","pmids":["16617148"],"is_preprint":false},{"year":2011,"finding":"Lats2 kinase interacts with Snail1 in the nucleus and directly phosphorylates Snail1 at residue T203, retaining Snail1 in the nucleus and thereby enhancing its stability and EMT-inducing activity.","method":"In vitro kinase assay, Co-IP, phosphorylation site mutagenesis, live-cell bioluminescence screen, in vivo zebrafish and mouse embryo models","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, mutagenesis, Co-IP, validated in vivo in two model organisms","pmids":["21952048"],"is_preprint":false},{"year":2011,"finding":"PARP-1 poly(ADP-ribosyl)ates Snail1 both in vitro and in vivo, interacting with Snail1 and stabilizing its protein levels; PARP inhibition downregulates Snail1 protein stability and suppresses EMT phenotypes.","method":"In vitro and in vivo poly(ADP-ribosyl)ation assay, Co-IP, knockdown, EMT phenotypic assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro and in vivo enzymatic assay, Co-IP, single lab","pmids":["21577210"],"is_preprint":false},{"year":2013,"finding":"FBXL5 is a nuclear E3 ubiquitin ligase that interacts with Snail1 in the nucleus, promoting its polyubiquitination and impairing its DNA binding; Snail1 is subsequently degraded in the cytosol. Lats2-mediated phosphorylation of Snail1 prevents its nuclear export but not its polyubiquitination by FBXL5.","method":"shRNA screening, Co-IP, ubiquitination assay, subcellular fractionation, mutagenesis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis with Lats2, functional DNA-binding assay, single lab with multiple orthogonal methods","pmids":["24157836"],"is_preprint":false},{"year":2019,"finding":"aPKC kinases of the PAR polarity complex phosphorylate SNAI1 at S249 under intact apical-basal polarity conditions, promoting SNAI1 protein degradation; loss of polarity prevents aPKC-mediated phosphorylation, stabilizing SNAI1 and promoting EMT.","method":"3D organoid cultures, phosphorylation site mutagenesis, loss-of-function of PAR complex components, xenograft models, human tissue correlation","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphorylation site mutagenesis, organoid functional assay, in vivo xenograft, human tissue validation","pmids":["30804505"],"is_preprint":false},{"year":2018,"finding":"USP27X is a deubiquitinase that directly increases Snail1 stability by counteracting its ubiquitination; USP27X is upregulated by TGFβ during EMT and is required for TGFβ-induced Snail1 expression, cell migration, invasion, and metastasis.","method":"siRNA screen, Co-IP, deubiquitination assay, knockdown/overexpression, in vitro invasion, in vivo metastasis assay","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA screen, deubiquitination assay, Co-IP, in vitro and in vivo functional validation, single lab with multiple orthogonal methods","pmids":["30341066"],"is_preprint":false},{"year":2019,"finding":"UDP-glucose inhibits SNAI1 mRNA stability by directly binding to HuR (Hu antigen R), preventing HuR from associating with SNAI1 mRNA; EGFR activation leads to UGDH phosphorylation at Y473, promoting conversion of UDP-glucose to UDP-glucuronic acid, relieving UDP-glucose inhibition and stabilizing SNAI1 mRNA to promote EMT and metastasis.","method":"RNA-protein interaction assay, mRNA stability assay, phosphorylation studies, in vitro and in vivo lung cancer models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical interaction assay, mRNA decay assay, phosphorylation mapping, in vivo validation, multiple methods in single rigorous study","pmids":["31243371"],"is_preprint":false},{"year":2008,"finding":"HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression; HMGA2 physically interacts with Smad proteins and cooperates with TGFβ/Smad signaling to increase Smad binding to the SNAIL1 promoter, inducing SNAIL1 expression and EMT.","method":"ChIP, promoter-reporter assays, Co-IP, siRNA knockdown, EMT phenotypic assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, promoter reporter, epistasis via knockdown, single lab with multiple orthogonal methods","pmids":["18832382"],"is_preprint":false},{"year":2010,"finding":"Phosphorylation of p68 RNA helicase at Y593 activates transcription of the Snail1 gene by promoting dissociation of HDAC1 from the Snail1 promoter; p68 interacts with the MBD3:Mi-2/NuRD chromatin remodeling complex.","method":"ChIP, Co-IP, promoter-reporter assay, mutagenesis of phosphorylation site","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, reporter assay, phosphorylation site mutagenesis, single lab","pmids":["20676135"],"is_preprint":false},{"year":2017,"finding":"TGFβ induces Smad3 recruitment of SETDB1 (histone H3K9 methyltransferase) to the SNAI1 gene locus, where SETDB1 deposits H3K9 methylation opposing Smad3/4-driven H3K9 acetylation, thereby repressing SNAI1 transcription and inhibiting EMT.","method":"ChIP, Co-IP, knockdown/overexpression, histone modification analysis","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, functional knockdown, single lab","pmids":["29233829"],"is_preprint":false},{"year":2023,"finding":"Lactate induces association between CBP/p300 and Snail1, leading to lactylation of Snail1 in a monocarboxylate transporter (MCT)-dependent manner; lactylated Snail1 promotes EndoMT and TGF-β/Smad2 pathway activation following hypoxia/myocardial infarction.","method":"Co-IP, lactylation assay, MCT inhibitor, siRNA knockdown, in vivo MI model","journal":"Science Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, biochemical lactylation assay, genetic and pharmacological knockdown, in vivo validation, single lab","pmids":["36735787"],"is_preprint":false},{"year":2024,"finding":"RHOF promotes PKM2 transcription via c-Myc, enhancing glycolysis and lactate production, which induces lactylation and nuclear translocation of Snail1, thereby driving EMT in pancreatic cancer cells.","method":"Western blotting, Co-IP, overexpression/knockdown, xenograft model, lactylation assay","journal":"Cancer & Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical assays, Co-IP, functional rescue, in vivo xenograft, single lab","pmids":["39462429"],"is_preprint":false},{"year":2011,"finding":"HIF-1α and HIF-2α directly activate Snail transcription through a hypoxia-response element (HRE) in the Snail gene promoter; gel shift and ChIP assays confirmed HIF binding to this HRE in vitro and in vivo.","method":"Gel shift (EMSA), ChIP, reporter gene assay, siRNA knockdown, HIF-ΔODD overexpression","journal":"Molecular Cancer Research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — EMSA, ChIP, reporter assay with mutagenesis, genetic gain/loss of function, single lab with multiple orthogonal methods","pmids":["21257819"],"is_preprint":false},{"year":2019,"finding":"SNAIL1 employs β-Catenin-LEF1 complexes as downstream effectors: SNAIL1 upregulates LEF1 expression, and LEF1 together with β-Catenin redirects Wnt/β-Catenin signaling toward pro-invasive gene expression; LEF1 knockout or β-Catenin-binding-deficient LEF1 impairs SNAIL1-driven invasion without affecting full EMT.","method":"CRISPR/Cas9 knockout, conditional SNAIL1 expression, transcriptome analysis, xenotransplantation","journal":"International Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO, rescue with mutant LEF1, transcriptomics, in vivo xenotransplantation, single lab","pmids":["31463973"],"is_preprint":false},{"year":2001,"finding":"Snail (SnaH) directly binds to a regulatory region (5'-CTGATGAAGT-3') near promoter I.3 of the human aromatase gene and represses its activity; the N-terminal SNAG domain of Snail is required for this repressor activity.","method":"Yeast one-hybrid screen, DNA mobility shift assay, mutagenesis, mammalian cell transfection/reporter assay, stable cell line with aromatase mRNA measurement","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast one-hybrid, EMSA with mutagenesis, reporter assay, SNAG-domain mutagenesis, functional mRNA measurement, single lab multiple orthogonal methods","pmids":["11245431"],"is_preprint":false},{"year":2012,"finding":"CK2 holoenzyme (requiring the CK2β regulatory subunit) negatively regulates Snail1 stability through synergistic hierarchical phosphorylation in concert with GSK3β; loss of CK2β relieves this suppression, inducing Snail1 accumulation and EMT.","method":"Overexpression/knockdown, phosphorylation assays, stability assays, EMT phenotypic assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis between CK2 and GSK3β, Snail1 stability assays, single lab","pmids":["22562247"],"is_preprint":false},{"year":2019,"finding":"SNAI1 recruits HDAC1 and HDAC2 to E-box sequences in the SNAI2 promoter to repress SNAI2 transcription through histone deacetylation.","method":"ChIP, HDAC inhibitor treatment, Co-IP, luciferase reporter assay, overexpression","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with multiple E-box sites, histone deacetylation measurement, HDAC inhibitor epistasis, single lab","pmids":["31165775"],"is_preprint":false},{"year":2018,"finding":"Snail1 binds to the TERT promoter and TERRA loci and represses telomerase (TERT) and telomeric repeat-containing RNA (TERRA) expression, thereby controlling telomere integrity in mesenchymal stem cells.","method":"FISH, ChIP, RNA expression analysis, conditional Snail1 depletion, telomerase activity assay","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, FISH, conditional KO, telomerase activity assay, single lab","pmids":["29059385"],"is_preprint":false},{"year":2013,"finding":"Snail1 directly binds to the promoter of the Cezanne2 gene via ChIP and mediates its transcriptional repression in hepatocellular carcinoma.","method":"ChIP, reporter gene assay, Co-immunoprecipitation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay, Co-IP for complex, single lab","pmids":["23792447"],"is_preprint":false},{"year":2009,"finding":"Mesenchymal cells (fibroblasts) reactivate Snail1 expression in response to proliferative/invasive agonists; Snail1-deficient fibroblasts show defects in MT1-MMP-dependent 3D invasive activity and fail to invade or induce angiogenesis in the chick CAM assay.","method":"Conditional Snai1 knockout, 3D ECM invasion assay, gene expression profiling, chick CAM model","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined phenotypic readout (MT1-MMP invasion), in vivo CAM model, genome-wide expression analysis","pmids":["19188491"],"is_preprint":false},{"year":2016,"finding":"ECM stiffness induces ROCK activity, which increases intracellular tension and integrin signaling to ERK2, leading to nuclear accumulation and stabilization of SNAIL1 in breast tumor cells and cancer-associated fibroblasts; SNAIL1 is required for the fibrogenic response of CAFs to stiff matrix and also influences YAP1 levels/activity.","method":"In vitro stiffness-tunable matrices, ROCK inhibition, ERK2 knockdown, SNAIL1 knockdown, in vivo breast tumor model","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanical perturbation experiments, kinase inhibition epistasis, SNAIL1 KD with defined fibrogenic phenotype, single lab","pmids":["27076520"],"is_preprint":false},{"year":2018,"finding":"Snail1 binds to the fatty acid synthase (FASN) promoter and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27, thereby repressing FASN promoter activity and suppressing lipogenesis in hepatocytes; this represents a non-canonical insulin-Snail1 pathway.","method":"ChIP, hepatocyte-specific Snail1 knockout, overexpression, promoter-reporter assay, metabolic phenotyping in vivo","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, conditional KO, overexpression rescue, multiple metabolic readouts, in vivo mouse model, single lab with multiple orthogonal methods","pmids":["30013137"],"is_preprint":false},{"year":2016,"finding":"Adipocyte Snail1 suppresses ATGL expression by binding to the ATGL promoter, repressing lipolysis; adipocyte-specific Snail1 deletion increases ATGL expression and lipolysis, causing decreased fat mass and increased liver fat.","method":"ChIP, adipocyte-specific conditional Snail1 knockout, ATGL promoter-reporter assay, metabolic phenotyping","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, conditional KO with specific metabolic phenotype, reporter assay, single lab with multiple orthogonal methods","pmids":["27851965"],"is_preprint":false},{"year":2015,"finding":"Conditional knockout of Snai1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells, bias toward secretory lineage differentiation, and failure to mount a proliferative response to radiation-induced damage, establishing a required role for Snai1 in intestinal stem cell maintenance and lineage choice.","method":"Conditional Snai1 knockout, intestinal organoid cultures, in vivo radiation damage model, lineage tracing","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined stem cell and lineage phenotype, organoid culture, in vivo radiation model, multiple readouts","pmids":["25759216"],"is_preprint":false},{"year":2014,"finding":"During embryonic stem cell differentiation, an endogenous Wnt-mediated increase in Snail1 expression regulates neuroectodermal fate and is required for epiblast stem cell exit and mesoderm commitment, independently of EMT.","method":"Isogenic pairs of conditional knockout mouse ESCs, transcriptome analysis, differentiation assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, transcriptome, functional differentiation assays, single lab","pmids":["24401905"],"is_preprint":false},{"year":2014,"finding":"Drosophila Snail can potentiate transcriptional activation (in addition to repression) by collaborating with Twist at co-occupied enhancers in the mesoderm; an enriched cis-regulatory motif distinct from E-boxes was identified as essential for enhancer activation.","method":"In vivo occupancy mapping (ChIP), expression profiling of staged snail mutant embryos, in vitro enhancer activation assay, in vivo enhancer reporter assay, machine learning motif analysis, in silico mutagenesis","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, in vivo and in vitro enhancer assays, mutagenesis, expression profiling in null mutants, multiple orthogonal methods","pmids":["24402316"],"is_preprint":false},{"year":2022,"finding":"MACC1 directly binds to SNAI1 protein and upregulates SNAI1 transcriptional activity, leading to transactivation of FN1 and trans-repression of CDH1, driving EMT and pancreatic cancer metastasis in a MET-independent manner.","method":"Co-IP, reporter gene assay, MACC1 overexpression/knockdown, liver metastasis mouse model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, in vivo liver metastasis model, single lab","pmids":["36333284"],"is_preprint":false},{"year":2021,"finding":"STK39 (a serine/threonine kinase) interacts with and phosphorylates SNAI1 at T203, promoting SNAI1 nuclear retention and stability; STK39 inhibition destabilizes SNAI1, impairs EMT, and reduces metastasis.","method":"Co-IP, in vitro kinase assay, phosphorylation site mutagenesis, knockdown/overexpression, in vitro invasion assay, in vivo metastasis model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro kinase assay, site mutagenesis, in vivo validation, single lab","pmids":["34335956"],"is_preprint":false},{"year":2023,"finding":"Ribotoxic stress activates JNK, which activates USP36, leading to USP36-mediated stabilization of Snail1 in the nucleolus; nucleolar Snail1 facilitates ribosome biogenesis and solid tumor cell survival, conferring resistance to homoharringtonine (HHT).","method":"JNK inhibition, USP36 knockdown, nucleolar fractionation, ribosome biogenesis assay, Co-IP, in vivo tumor model","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis (JNK-USP36-Snail1), subcellular fractionation, in vivo validation, single lab","pmids":["37833415"],"is_preprint":false},{"year":2022,"finding":"USP9X deubiquitinates and stabilizes Snail1 protein; depletion or pharmacological inhibition of USP9X downregulates Snail1, inhibits cell migration, invasion, and metastasis, and sensitizes triple-negative breast cancer cells to cisplatin and paclitaxel.","method":"Co-IP, deubiquitination assay, knockdown/inhibitor, rescue with Snail1 overexpression, in vitro invasion assay, in vivo metastasis model","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay, Co-IP, rescue experiment, in vivo validation, single lab","pmids":["35506169"],"is_preprint":false},{"year":2020,"finding":"USP18 deubiquitinates and stabilizes Snail1 protein in colorectal cancer; USP18 interacts with Snail1, and its overexpression promotes proliferation, migration, and invasion that is reversed by Snail1 knockdown.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, rescue experiment","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue, single lab","pmids":["32742193"],"is_preprint":false},{"year":2020,"finding":"USP22 deubiquitinates and stabilizes Snail1 protein in renal tubular epithelial cells; USP22 depletion reduces Snail1 levels, inhibits EMT, and improves renal pathology in diabetic mice.","method":"Co-IP, deubiquitination assay, USP22 knockdown/overexpression, in vivo db/db diabetic mouse model","journal":"European Journal of Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay, Co-IP, in vivo diabetic model, single lab","pmids":["37001578"],"is_preprint":false},{"year":2020,"finding":"TRIM2 deubiquitinates and stabilizes Snail1 protein in lung adenocarcinoma; TRIM2 interacts with Snail1 via Co-IP and regulates Snail1 ubiquitination-dependent degradation to promote proliferation and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown","journal":"Cancer Cell International","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, limited mechanistic follow-up","pmids":["32536816"],"is_preprint":false},{"year":2013,"finding":"During chondrogenesis, endogenous SNAI1 and SNAI2 proteins bind to E2-box sequences in both their own and each other's promoters, providing a molecular mechanism for compensatory transcriptional regulation between Snai1 and Snai2 during long bone development.","method":"ChIP in differentiating ATDC5 cells, conditional double knockout mouse model","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with endogenous proteins, genetic epistasis via double KO, single lab","pmids":["23665016"],"is_preprint":false},{"year":2015,"finding":"GBS and other meningeal pathogens induce Snail1 expression in human brain microvascular endothelial cells via ERK1/2/MAPK signaling and bacterial cell wall components; Snail1 then represses tight junction genes (ZO-1, claudin 5, occludin) at the transcriptional level, facilitating blood-brain barrier disruption and bacterial penetration.","method":"Snail1 knockdown/overexpression, dominant-negative Snail1 in zebrafish, ERK1/2 inhibition, tight junction mRNA/protein measurement","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown, dominant-negative, in vivo zebrafish model, pathway epistasis, multiple orthogonal assays","pmids":["25961453"],"is_preprint":false},{"year":2018,"finding":"The transcription factor scleraxis directly binds E-box sequences in the Snai1 promoter to transactivate Snai1 gene expression; TGFβ-mediated upregulation of Snai1 is completely dependent on scleraxis.","method":"ChIP, promoter-reporter assay, scleraxis knockdown/overexpression, epistasis with TGFβ signaling","journal":"American Journal of Physiology. Heart and Circulatory Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, epistasis, single lab","pmids":["29906225"],"is_preprint":false},{"year":2010,"finding":"Snail1 and Snail2 directly repress vitamin D receptor (VDR) gene promoter activity; this repression is specific to the Snail family, as other EMT-inducing transcription factors do not affect VDR expression in colon cancer cells.","method":"Promoter-reporter assay, overexpression in colon cancer cells, specificity comparison across EMT transcription factors","journal":"The Journal of Steroid Biochemistry and Molecular Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay only, no ChIP or mutagenesis, single lab","pmids":["20138990"],"is_preprint":false},{"year":2019,"finding":"SNAI1 represses SNAI2 transcription by binding to E-box sequences in the SNAI2 promoter and recruiting HDAC1 to mediate histone deacetylation.","method":"ChIP, HDAC inhibitor assay, overexpression, luciferase reporter","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, histone modification assay, reporter, single lab","pmids":["31165775"],"is_preprint":false},{"year":2014,"finding":"Transient (but not continuous) SNAIL1 expression in breast cancer primary tumors is sufficient and required to increase metastasis in immunocompetent mouse models; SNAIL1 gene deletion before or after tumor formation blunts metastasis.","method":"Genetic SNAIL1 reporter-transgene model, inducible SNAIL1 expression/deletion, multiple immunocompetent breast cancer mouse models","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model, inducible transgene, multiple mouse models, direct mechanistic insight into temporal requirement","pmids":["25164016"],"is_preprint":false},{"year":2020,"finding":"Acetate promotes SNAI1 expression under glucose limitation via ACSS2-mediated histone H3K27 acetylation at the SNAI1 regulatory region; ACSS2 knockdown abolishes acetate-induced SNAI1 upregulation and cell migration.","method":"ChIP, siRNA knockdown, overexpression, qRT-PCR, migration assay","journal":"Bioscience Reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and knockdown in single lab, limited orthogonal validation","pmids":["32458971"],"is_preprint":false}],"current_model":"SNAI1 (Snail1) is a zinc-finger transcriptional repressor and context-dependent activator that drives epithelial-mesenchymal transition primarily by recruiting epigenetic co-repressor complexes (LSD1/HDAC1, G9a/DNMTs, HDAC1/2, SETDB1) to E-box elements at target promoters (CDH1, SNAI2, ATGL, FASN, VDR, tight junction genes); its protein stability and nuclear retention are tightly regulated by a network of kinases (ERK2 downstream of DDR2/Src/ROCK, Lats2, aPKC, STK39, CK2/GSK3β) that phosphorylate specific residues to control nuclear localization and ubiquitin-mediated degradation, as well as by multiple deubiquitinases (USP27X, USP9X, USP18, USP22, USP36, TRIM2) that stabilize it; Snail1 is subject to additional post-translational modifications including poly(ADP-ribosyl)ation by PARP-1 and lactylation by CBP/p300; its mRNA stability is regulated by HuR/UDP-glucose; beyond EMT, Snail1 regulates intestinal stem cell maintenance, neuroectodermal fate in ESCs, telomere integrity, lipid metabolism in liver and adipose tissue, ribosome biogenesis under ribotoxic stress, and blood-brain barrier integrity."},"narrative":{"mechanistic_narrative":"SNAI1 (Snail1) is a SNAG-domain zinc-finger transcription factor that acts principally as a sequence-specific transcriptional repressor at E-box elements and is the central effector of epithelial-mesenchymal transition (EMT) [PMID:22406531, PMID:11245431]. Repression is achieved by recruiting epigenetic co-repressor machinery to target promoters: Snail1 binds G9a and DNA methyltransferases to deposit H3K9me2 and DNA methylation at the E-cadherin promoter [PMID:22406531], and engages HDAC1/2 to deacetylate histones at the SNAI2, FASN, and other loci [PMID:31165775, PMID:30013137]. Through these activities Snail1 controls a broad target program — silencing CDH1, tight-junction genes (ZO-1, claudin 5, occludin), VDR, telomerase (TERT/TERRA), and lipid-handling genes (FASN, ATGL) — and can also potentiate transcriptional activation when partnered at co-occupied enhancers [PMID:24402316, PMID:25961453, PMID:29059385, PMID:30013137, PMID:27851965]. Snail1 additionally autoregulates and cross-regulates within the Snail family, repressing its own and SNAI2 promoters through E-box binding [PMID:16617148, PMID:23665016, PMID:31165775]. Snail1 abundance and nuclear retention are governed by an extensive post-translational network: phosphorylation by ERK2 (downstream of DDR2/Src and ECM stiffness/ROCK), Lats2 and STK39 at T203, and aPKC at S249 dictates nuclear accumulation versus FBXL5/CK2-GSK3β-driven ubiquitination and degradation [PMID:23644467, PMID:21952048, PMID:34335956, PMID:30804505, PMID:24157836, PMID:22562247, PMID:27076520], while a panel of deubiquitinases (USP27X, USP9X, USP18, USP22, USP36) and PARP-1-mediated poly(ADP-ribosyl)ation stabilize the protein [PMID:30341066, PMID:35506169, PMID:32742193, PMID:37001578, PMID:37833415, PMID:21577210]. Upstream, Snail1 transcription is induced by TGFβ/Smad cooperating with HMGA2, by HIF-1α/2α under hypoxia, and by lactate/acetate-driven chromatin modification, and its mRNA stability is set by HuR sensing of UDP-glucose [PMID:18832382, PMID:21257819, PMID:36735787, PMID:32458971, PMID:31243371]. Beyond EMT and metastasis [PMID:25164016, PMID:19188491], Snail1 is required for intestinal stem cell maintenance and lineage choice, neuroectodermal fate during ESC differentiation, hepatic and adipocyte lipid metabolism, nucleolar ribosome biogenesis under ribotoxic stress, and blood-brain barrier integrity [PMID:25759216, PMID:24401905, PMID:30013137, PMID:27851965, PMID:37833415, PMID:25961453].","teleology":[{"year":2001,"claim":"Established that Snail functions as a direct, sequence-specific transcriptional repressor whose activity depends on its N-terminal SNAG domain, defining its core molecular mechanism beyond E-cadherin.","evidence":"Yeast one-hybrid, EMSA with mutagenesis, and SNAG-domain mutant reporter assays at the aromatase promoter","pmids":["11245431"],"confidence":"High","gaps":["Did not identify the co-repressors recruited via the SNAG domain","Single target gene context"]},{"year":2006,"claim":"Showed Snail1 negatively autoregulates its own promoter, revealing a feedback loop that bounds Snail1 levels.","evidence":"ChIP, promoter-reporter assays, and E-box mutagenesis","pmids":["16617148"],"confidence":"High","gaps":["Quantitative impact of the loop on EMT dynamics not defined","Co-repressors at the autoregulated promoter not identified"]},{"year":2012,"claim":"Identified the epigenetic effectors of Snail1 repression, linking it to histone H3K9 methylation and DNA methylation at the E-cadherin promoter.","evidence":"Reciprocal Co-IP, ChIP, and knockdown across EMT models showing G9a/DNMT recruitment","pmids":["22406531"],"confidence":"High","gaps":["Whether G9a/DNMT recruitment generalizes to all Snail1 targets unknown","Order of H3K9me2 versus DNA methylation deposition not resolved"]},{"year":2011,"claim":"Defined how kinase signaling controls Snail1 nuclear retention and stability, with Lats2 phosphorylation at T203 promoting nuclear retention and EMT activity.","evidence":"In vitro kinase assay, Co-IP, T203 mutagenesis, and in vivo zebrafish/mouse models","pmids":["21952048"],"confidence":"High","gaps":["How the same T203 site integrates inputs from other kinases not addressed","Relationship to nuclear export machinery unresolved at this stage"]},{"year":2013,"claim":"Connected extracellular collagen sensing to Snail1 stabilization, showing DDR2-Src-ERK2 directly phosphorylates Snail1 to extend its half-life and drive metastasis.","evidence":"In vitro kinase assay, phosphosite mapping, ubiquitylation assays, and in vivo metastasis models","pmids":["23644467"],"confidence":"High","gaps":["Precise ERK2 phosphosite-to-ubiquitin-machinery link not fully mapped","Crosstalk with degradative kinases not integrated"]},{"year":2013,"claim":"Identified FBXL5 as the nuclear E3 ligase that ubiquitinates Snail1 and impairs its DNA binding, and clarified that Lats2 phosphorylation blocks export but not ubiquitination.","evidence":"shRNA screen, Co-IP, ubiquitination and DNA-binding assays, subcellular fractionation, epistasis with Lats2","pmids":["24157836"],"confidence":"High","gaps":["Whether cytosolic degradation uses a distinct ligase unresolved","Stoichiometry of phosphorylation versus ubiquitination not quantified"]},{"year":2019,"claim":"Linked epithelial polarity to Snail1 turnover, showing aPKC phosphorylation at S249 degrades Snail1 when polarity is intact, and loss of polarity stabilizes it to license EMT.","evidence":"3D organoids, S249 mutagenesis, PAR-complex loss-of-function, xenografts, human tissue correlation","pmids":["30804505"],"confidence":"High","gaps":["Ligase coupled to S249 phosphorylation not identified","Interplay between S249 and T203 phosphorylation not dissected"]},{"year":2018,"claim":"Established deubiquitination as a major Snail1-stabilizing mechanism, with USP27X required for TGFβ-induced Snail1 expression and metastasis.","evidence":"siRNA screen, Co-IP, deubiquitination assay, and in vitro/in vivo invasion-metastasis assays","pmids":["30341066"],"confidence":"High","gaps":["Specificity among multiple Snail1 DUBs not compared","Lysine residues targeted not mapped"]},{"year":2014,"claim":"Resolved the temporal requirement for Snail1 in metastasis, showing transient rather than continuous expression is sufficient and required to promote dissemination.","evidence":"Inducible SNAIL1 reporter-transgene and deletion in multiple immunocompetent breast cancer mouse models","pmids":["25164016"],"confidence":"High","gaps":["Molecular memory underlying transient-expression sufficiency not defined","Cell-of-origin dependence not resolved"]},{"year":2015,"claim":"Expanded Snail1 biology beyond cancer, establishing essential roles in intestinal stem cell maintenance, lineage choice, and damage response.","evidence":"Conditional intestinal Snai1 knockout, organoids, lineage tracing, and in vivo radiation model","pmids":["25759216"],"confidence":"High","gaps":["Direct target genes mediating stem cell survival not identified","Relationship to EMT program in this context unclear"]},{"year":2018,"claim":"Revealed non-EMT metabolic functions, showing Snail1 represses lipogenic and lipolytic genes (FASN, ATGL) via HDAC recruitment to control tissue lipid balance.","evidence":"ChIP, tissue-specific conditional knockouts, promoter-reporter assays, and metabolic phenotyping","pmids":["30013137","27851965"],"confidence":"High","gaps":["Signals that direct Snail1 to metabolic versus EMT promoters unknown","How insulin/non-canonical input couples to Snail1 not fully mapped"]},{"year":2023,"claim":"Identified lactylation as a metabolic post-translational mark on Snail1, with CBP/p300-mediated lactylation driving endothelial transition and EMT downstream of glycolysis.","evidence":"Co-IP, lactylation assays, MCT inhibition, and in vivo myocardial infarction and xenograft models","pmids":["36735787","39462429"],"confidence":"Medium","gaps":["Lactylated residues not definitively mapped","Functional interplay with phosphorylation/ubiquitination not addressed"]},{"year":2023,"claim":"Uncovered a nucleolar role for Snail1 in ribosome biogenesis under stress, with JNK-USP36 stabilizing nucleolar Snail1 to support tumor cell survival.","evidence":"JNK inhibition, USP36 knockdown, nucleolar fractionation, ribosome biogenesis assays, and in vivo tumor model","pmids":["37833415"],"confidence":"Medium","gaps":["Direct nucleolar targets/mechanism of ribosome biogenesis support unknown","Whether DNA/E-box binding is involved nucleolarly unclear"]},{"year":null,"claim":"How the dense network of competing kinases, ligases, deubiquitinases, and metabolic PTMs is integrated to set Snail1 dosage, residence, and target selectivity in a given tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of Snail1 PTM hierarchy","Determinants of repressor versus activator/enhancer behavior not defined","Context-specific target gene selection mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,16,18,23,24,27]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,16,19,35]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,5,6,29]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,16,18,23,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,26,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,14,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of 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Binds to 3 E-boxes of the E-cadherin/CDH1 gene promoter and to the promoters of CLDN7 and KRT8 and, in association with histone demethylase KDM1A which it recruits to the promoters, causes a decrease in dimethylated H3K4 levels and represses transcription (PubMed:10655587, PubMed:20389281, PubMed:20562920). The N-terminal SNAG domain competes with histone H3 for the same binding site on the histone demethylase complex formed by KDM1A and RCOR1, and thereby inhibits demethylation of histone H3 at 'Lys-4' (in vitro) (PubMed:20389281, PubMed:21300290, PubMed:23721412). During EMT, involved with LOXL2 in negatively regulating pericentromeric heterochromatin transcription (PubMed:16096638). SNAI1 recruits LOXL2 to pericentromeric regions to oxidize histone H3 and repress transcription which leads to release of heterochromatin component CBX5/HP1A, enabling chromatin reorganization and acquisition of mesenchymal traits (By similarity). Associates with EGR1 and SP1 to mediate tetradecanoyl phorbol acetate (TPA)-induced up-regulation of CDKN2B, possibly by binding to the CDKN2B promoter region 5'-TCACA-3 (PubMed:20121949). In addition, may also activate the CDKN2B promoter by itself (PubMed:20121949)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O95863/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNAI1","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNAI1","total_profiled":1310},"omim":[{"mim_id":"621546","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 22; TTC22","url":"https://www.omim.org/entry/621546"},{"mim_id":"618739","title":"CTD SMALL PHOSPHATASE-LIKE PROTEIN 2; CTDSPL2","url":"https://www.omim.org/entry/618739"},{"mim_id":"618703","title":"ZINC FINGER PROTEIN 281; ZNF281","url":"https://www.omim.org/entry/618703"},{"mim_id":"617438","title":"CHROMOBOX 6; CBX6","url":"https://www.omim.org/entry/617438"},{"mim_id":"614027","title":"INSULINOMA-ASSOCIATED 2; INSM2","url":"https://www.omim.org/entry/614027"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose 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carcinoma.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23792447","citation_count":32,"is_preprint":false},{"pmid":"21822727","id":"PMC_21822727","title":"Nematode and snail metallothioneins.","date":"2011","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21822727","citation_count":30,"is_preprint":false},{"pmid":"29906225","id":"PMC_29906225","title":"Scleraxis regulates Twist1 and Snai1 expression in the epithelial-to-mesenchymal transition.","date":"2018","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29906225","citation_count":30,"is_preprint":false},{"pmid":"35506169","id":"PMC_35506169","title":"Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple-negative breast cancer by stabilizing Snail1.","date":"2022","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35506169","citation_count":30,"is_preprint":false},{"pmid":"29059385","id":"PMC_29059385","title":"Snail1 transcription factor controls telomere transcription and integrity.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29059385","citation_count":29,"is_preprint":false},{"pmid":"14593479","id":"PMC_14593479","title":"Prospero and Snail expression during spider neurogenesis.","date":"2003","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/14593479","citation_count":29,"is_preprint":false},{"pmid":"32536816","id":"PMC_32536816","title":"TRIM2 directly deubiquitinates and stabilizes Snail1 protein, mediating proliferation and metastasis of lung adenocarcinoma.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32536816","citation_count":28,"is_preprint":false},{"pmid":"32696548","id":"PMC_32696548","title":"Nodakenin alleviated obstructive nephropathy through blunting Snail1 induced fibrosis.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32696548","citation_count":28,"is_preprint":false},{"pmid":"19695091","id":"PMC_19695091","title":"Nuclear expression of Snail1 in borderline and malignant epithelial ovarian tumours is associated with tumour progression.","date":"2009","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19695091","citation_count":28,"is_preprint":false},{"pmid":"37833415","id":"PMC_37833415","title":"USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37833415","citation_count":27,"is_preprint":false},{"pmid":"24947186","id":"PMC_24947186","title":"Snail1 expression is required for sarcomagenesis.","date":"2014","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24947186","citation_count":26,"is_preprint":false},{"pmid":"32458971","id":"PMC_32458971","title":"Acetate promotes SNAI1 expression by ACSS2-mediated histone acetylation under glucose limitation in renal cell carcinoma cell.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32458971","citation_count":26,"is_preprint":false},{"pmid":"30034631","id":"PMC_30034631","title":"The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30034631","citation_count":26,"is_preprint":false},{"pmid":"29729076","id":"PMC_29729076","title":"Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells.","date":"2018","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29729076","citation_count":25,"is_preprint":false},{"pmid":"33292457","id":"PMC_33292457","title":"The pond snail Lymnaea stagnalis.","date":"2020","source":"EvoDevo","url":"https://pubmed.ncbi.nlm.nih.gov/33292457","citation_count":23,"is_preprint":false},{"pmid":"27087845","id":"PMC_27087845","title":"What can be learnt from a snail?","date":"2015","source":"Evolutionary applications","url":"https://pubmed.ncbi.nlm.nih.gov/27087845","citation_count":23,"is_preprint":false},{"pmid":"21725924","id":"PMC_21725924","title":"Expression of transcription factor Snai1 and tubulointerstitial fibrosis in progressive nephropathy.","date":"2012","source":"Journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/21725924","citation_count":22,"is_preprint":false},{"pmid":"24959244","id":"PMC_24959244","title":"Transcription factor Snai1-1 induces osteosarcoma invasion and metastasis by inhibiting E-cadherin expression.","date":"2014","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/24959244","citation_count":22,"is_preprint":false},{"pmid":"35841383","id":"PMC_35841383","title":"LOXL3-promoted hepatocellular carcinoma progression via promotion of Snail1/USP4-mediated epithelial-mesenchymal transition.","date":"2022","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35841383","citation_count":21,"is_preprint":false},{"pmid":"30253797","id":"PMC_30253797","title":"Snail promotes metastasis of nasopharyngeal carcinoma partly by down-regulating TEL2.","date":"2018","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30253797","citation_count":21,"is_preprint":false},{"pmid":"17106264","id":"PMC_17106264","title":"Snail1 gene function during early embryo patterning in mice.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17106264","citation_count":21,"is_preprint":false},{"pmid":"23510993","id":"PMC_23510993","title":"MTA3 regulates CGB5 and Snail genes in trophoblast.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23510993","citation_count":21,"is_preprint":false},{"pmid":"23665016","id":"PMC_23665016","title":"The SNAI1 and SNAI2 proteins occupy their own and each other's promoter during chondrogenesis.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23665016","citation_count":19,"is_preprint":false},{"pmid":"37174625","id":"PMC_37174625","title":"IL-22-Activated MUC13 Impacts on Colonic Barrier Function through JAK1/STAT3, SNAI1/ZEB1 and ROCK2/MAPK Signaling.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37174625","citation_count":19,"is_preprint":false},{"pmid":"34335956","id":"PMC_34335956","title":"STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34335956","citation_count":19,"is_preprint":false},{"pmid":"30684287","id":"PMC_30684287","title":"PGC-1α/SNAI1 axis regulates tumor growth and metastasis by targeting miR-128b in gastric cancer.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30684287","citation_count":19,"is_preprint":false},{"pmid":"38043804","id":"PMC_38043804","title":"Dual role of Snail1 as transcriptional repressor and activator.","date":"2023","source":"Biochimica et biophysica acta. Reviews on cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38043804","citation_count":18,"is_preprint":false},{"pmid":"29147673","id":"PMC_29147673","title":"The regulation of snail: on the ubiquitin edge.","date":"2017","source":"Cancer cell & microenvironment","url":"https://pubmed.ncbi.nlm.nih.gov/29147673","citation_count":18,"is_preprint":false},{"pmid":"36290118","id":"PMC_36290118","title":"Edible Snail Production in Europe.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36290118","citation_count":17,"is_preprint":false},{"pmid":"36703369","id":"PMC_36703369","title":"Intrastrand backbone-nucleobase interactions stabilize unwound right-handed helical structures of heteroduplexes of L-aTNA/RNA and SNA/RNA.","date":"2020","source":"Communications chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36703369","citation_count":17,"is_preprint":false},{"pmid":"37001578","id":"PMC_37001578","title":"USP22 aggravated diabetic renal tubulointerstitial fibrosis progression through deubiquitinating and stabilizing Snail1.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37001578","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46569,"output_tokens":9270,"usd":0.139378,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19345,"output_tokens":4496,"usd":0.104563,"stage2_stop_reason":"end_turn"},"total_usd":0.243941,"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\": 2012,\n      \"finding\": \"Snail1 interacts with G9a (a major euchromatin H3K9 methyltransferase) and recruits G9a and DNA methyltransferases to the E-cadherin promoter, leading to H3K9me2 and subsequent DNA methylation-mediated repression of E-cadherin.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, knockdown assays, in vitro and in vivo EMT models\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, functional knockdown with defined phenotypic readout, replicated across multiple cell lines\",\n      \"pmids\": [\"22406531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Activation of the collagen I receptor DDR2 stimulates ERK2 activity in a Src-dependent manner; activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation, and increased protein half-life, thereby stabilizing SNAIL1 and promoting breast cancer metastasis.\",\n      \"method\": \"In vitro kinase assay, phosphorylation site mapping, ubiquitylation assays, Co-IP, in vivo metastasis models\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro phosphorylation, functional rescue experiments, in vivo validation\",\n      \"pmids\": [\"23644467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Snail1 protein binds to an E-box at −146 bp in its own promoter and represses its transcriptional activity, forming a negative feedback regulatory loop that limits Snail1 expression levels.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter-reporter assays, E-box mutagenesis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP with endogenous and ectopic protein, reporter assay, mutagenesis in single lab\",\n      \"pmids\": [\"16617148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lats2 kinase interacts with Snail1 in the nucleus and directly phosphorylates Snail1 at residue T203, retaining Snail1 in the nucleus and thereby enhancing its stability and EMT-inducing activity.\",\n      \"method\": \"In vitro kinase assay, Co-IP, phosphorylation site mutagenesis, live-cell bioluminescence screen, in vivo zebrafish and mouse embryo models\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, mutagenesis, Co-IP, validated in vivo in two model organisms\",\n      \"pmids\": [\"21952048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PARP-1 poly(ADP-ribosyl)ates Snail1 both in vitro and in vivo, interacting with Snail1 and stabilizing its protein levels; PARP inhibition downregulates Snail1 protein stability and suppresses EMT phenotypes.\",\n      \"method\": \"In vitro and in vivo poly(ADP-ribosyl)ation assay, Co-IP, knockdown, EMT phenotypic assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro and in vivo enzymatic assay, Co-IP, single lab\",\n      \"pmids\": [\"21577210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXL5 is a nuclear E3 ubiquitin ligase that interacts with Snail1 in the nucleus, promoting its polyubiquitination and impairing its DNA binding; Snail1 is subsequently degraded in the cytosol. Lats2-mediated phosphorylation of Snail1 prevents its nuclear export but not its polyubiquitination by FBXL5.\",\n      \"method\": \"shRNA screening, Co-IP, ubiquitination assay, subcellular fractionation, mutagenesis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis with Lats2, functional DNA-binding assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24157836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"aPKC kinases of the PAR polarity complex phosphorylate SNAI1 at S249 under intact apical-basal polarity conditions, promoting SNAI1 protein degradation; loss of polarity prevents aPKC-mediated phosphorylation, stabilizing SNAI1 and promoting EMT.\",\n      \"method\": \"3D organoid cultures, phosphorylation site mutagenesis, loss-of-function of PAR complex components, xenograft models, human tissue correlation\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphorylation site mutagenesis, organoid functional assay, in vivo xenograft, human tissue validation\",\n      \"pmids\": [\"30804505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP27X is a deubiquitinase that directly increases Snail1 stability by counteracting its ubiquitination; USP27X is upregulated by TGFβ during EMT and is required for TGFβ-induced Snail1 expression, cell migration, invasion, and metastasis.\",\n      \"method\": \"siRNA screen, Co-IP, deubiquitination assay, knockdown/overexpression, in vitro invasion, in vivo metastasis assay\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen, deubiquitination assay, Co-IP, in vitro and in vivo functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30341066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UDP-glucose inhibits SNAI1 mRNA stability by directly binding to HuR (Hu antigen R), preventing HuR from associating with SNAI1 mRNA; EGFR activation leads to UGDH phosphorylation at Y473, promoting conversion of UDP-glucose to UDP-glucuronic acid, relieving UDP-glucose inhibition and stabilizing SNAI1 mRNA to promote EMT and metastasis.\",\n      \"method\": \"RNA-protein interaction assay, mRNA stability assay, phosphorylation studies, in vitro and in vivo lung cancer models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical interaction assay, mRNA decay assay, phosphorylation mapping, in vivo validation, multiple methods in single rigorous study\",\n      \"pmids\": [\"31243371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression; HMGA2 physically interacts with Smad proteins and cooperates with TGFβ/Smad signaling to increase Smad binding to the SNAIL1 promoter, inducing SNAIL1 expression and EMT.\",\n      \"method\": \"ChIP, promoter-reporter assays, Co-IP, siRNA knockdown, EMT phenotypic assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, promoter reporter, epistasis via knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18832382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Phosphorylation of p68 RNA helicase at Y593 activates transcription of the Snail1 gene by promoting dissociation of HDAC1 from the Snail1 promoter; p68 interacts with the MBD3:Mi-2/NuRD chromatin remodeling complex.\",\n      \"method\": \"ChIP, Co-IP, promoter-reporter assay, mutagenesis of phosphorylation site\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, reporter assay, phosphorylation site mutagenesis, single lab\",\n      \"pmids\": [\"20676135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGFβ induces Smad3 recruitment of SETDB1 (histone H3K9 methyltransferase) to the SNAI1 gene locus, where SETDB1 deposits H3K9 methylation opposing Smad3/4-driven H3K9 acetylation, thereby repressing SNAI1 transcription and inhibiting EMT.\",\n      \"method\": \"ChIP, Co-IP, knockdown/overexpression, histone modification analysis\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, functional knockdown, single lab\",\n      \"pmids\": [\"29233829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Lactate induces association between CBP/p300 and Snail1, leading to lactylation of Snail1 in a monocarboxylate transporter (MCT)-dependent manner; lactylated Snail1 promotes EndoMT and TGF-β/Smad2 pathway activation following hypoxia/myocardial infarction.\",\n      \"method\": \"Co-IP, lactylation assay, MCT inhibitor, siRNA knockdown, in vivo MI model\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, biochemical lactylation assay, genetic and pharmacological knockdown, in vivo validation, single lab\",\n      \"pmids\": [\"36735787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RHOF promotes PKM2 transcription via c-Myc, enhancing glycolysis and lactate production, which induces lactylation and nuclear translocation of Snail1, thereby driving EMT in pancreatic cancer cells.\",\n      \"method\": \"Western blotting, Co-IP, overexpression/knockdown, xenograft model, lactylation assay\",\n      \"journal\": \"Cancer & Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical assays, Co-IP, functional rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"39462429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HIF-1α and HIF-2α directly activate Snail transcription through a hypoxia-response element (HRE) in the Snail gene promoter; gel shift and ChIP assays confirmed HIF binding to this HRE in vitro and in vivo.\",\n      \"method\": \"Gel shift (EMSA), ChIP, reporter gene assay, siRNA knockdown, HIF-ΔODD overexpression\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA, ChIP, reporter assay with mutagenesis, genetic gain/loss of function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21257819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNAIL1 employs β-Catenin-LEF1 complexes as downstream effectors: SNAIL1 upregulates LEF1 expression, and LEF1 together with β-Catenin redirects Wnt/β-Catenin signaling toward pro-invasive gene expression; LEF1 knockout or β-Catenin-binding-deficient LEF1 impairs SNAIL1-driven invasion without affecting full EMT.\",\n      \"method\": \"CRISPR/Cas9 knockout, conditional SNAIL1 expression, transcriptome analysis, xenotransplantation\",\n      \"journal\": \"International Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO, rescue with mutant LEF1, transcriptomics, in vivo xenotransplantation, single lab\",\n      \"pmids\": [\"31463973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Snail (SnaH) directly binds to a regulatory region (5'-CTGATGAAGT-3') near promoter I.3 of the human aromatase gene and represses its activity; the N-terminal SNAG domain of Snail is required for this repressor activity.\",\n      \"method\": \"Yeast one-hybrid screen, DNA mobility shift assay, mutagenesis, mammalian cell transfection/reporter assay, stable cell line with aromatase mRNA measurement\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast one-hybrid, EMSA with mutagenesis, reporter assay, SNAG-domain mutagenesis, functional mRNA measurement, single lab multiple orthogonal methods\",\n      \"pmids\": [\"11245431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CK2 holoenzyme (requiring the CK2β regulatory subunit) negatively regulates Snail1 stability through synergistic hierarchical phosphorylation in concert with GSK3β; loss of CK2β relieves this suppression, inducing Snail1 accumulation and EMT.\",\n      \"method\": \"Overexpression/knockdown, phosphorylation assays, stability assays, EMT phenotypic assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis between CK2 and GSK3β, Snail1 stability assays, single lab\",\n      \"pmids\": [\"22562247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNAI1 recruits HDAC1 and HDAC2 to E-box sequences in the SNAI2 promoter to repress SNAI2 transcription through histone deacetylation.\",\n      \"method\": \"ChIP, HDAC inhibitor treatment, Co-IP, luciferase reporter assay, overexpression\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with multiple E-box sites, histone deacetylation measurement, HDAC inhibitor epistasis, single lab\",\n      \"pmids\": [\"31165775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Snail1 binds to the TERT promoter and TERRA loci and represses telomerase (TERT) and telomeric repeat-containing RNA (TERRA) expression, thereby controlling telomere integrity in mesenchymal stem cells.\",\n      \"method\": \"FISH, ChIP, RNA expression analysis, conditional Snail1 depletion, telomerase activity assay\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, FISH, conditional KO, telomerase activity assay, single lab\",\n      \"pmids\": [\"29059385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Snail1 directly binds to the promoter of the Cezanne2 gene via ChIP and mediates its transcriptional repression in hepatocellular carcinoma.\",\n      \"method\": \"ChIP, reporter gene assay, Co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay, Co-IP for complex, single lab\",\n      \"pmids\": [\"23792447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mesenchymal cells (fibroblasts) reactivate Snail1 expression in response to proliferative/invasive agonists; Snail1-deficient fibroblasts show defects in MT1-MMP-dependent 3D invasive activity and fail to invade or induce angiogenesis in the chick CAM assay.\",\n      \"method\": \"Conditional Snai1 knockout, 3D ECM invasion assay, gene expression profiling, chick CAM model\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined phenotypic readout (MT1-MMP invasion), in vivo CAM model, genome-wide expression analysis\",\n      \"pmids\": [\"19188491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ECM stiffness induces ROCK activity, which increases intracellular tension and integrin signaling to ERK2, leading to nuclear accumulation and stabilization of SNAIL1 in breast tumor cells and cancer-associated fibroblasts; SNAIL1 is required for the fibrogenic response of CAFs to stiff matrix and also influences YAP1 levels/activity.\",\n      \"method\": \"In vitro stiffness-tunable matrices, ROCK inhibition, ERK2 knockdown, SNAIL1 knockdown, in vivo breast tumor model\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanical perturbation experiments, kinase inhibition epistasis, SNAIL1 KD with defined fibrogenic phenotype, single lab\",\n      \"pmids\": [\"27076520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Snail1 binds to the fatty acid synthase (FASN) promoter and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27, thereby repressing FASN promoter activity and suppressing lipogenesis in hepatocytes; this represents a non-canonical insulin-Snail1 pathway.\",\n      \"method\": \"ChIP, hepatocyte-specific Snail1 knockout, overexpression, promoter-reporter assay, metabolic phenotyping in vivo\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, conditional KO, overexpression rescue, multiple metabolic readouts, in vivo mouse model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30013137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adipocyte Snail1 suppresses ATGL expression by binding to the ATGL promoter, repressing lipolysis; adipocyte-specific Snail1 deletion increases ATGL expression and lipolysis, causing decreased fat mass and increased liver fat.\",\n      \"method\": \"ChIP, adipocyte-specific conditional Snail1 knockout, ATGL promoter-reporter assay, metabolic phenotyping\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, conditional KO with specific metabolic phenotype, reporter assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27851965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional knockout of Snai1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells, bias toward secretory lineage differentiation, and failure to mount a proliferative response to radiation-induced damage, establishing a required role for Snai1 in intestinal stem cell maintenance and lineage choice.\",\n      \"method\": \"Conditional Snai1 knockout, intestinal organoid cultures, in vivo radiation damage model, lineage tracing\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined stem cell and lineage phenotype, organoid culture, in vivo radiation model, multiple readouts\",\n      \"pmids\": [\"25759216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"During embryonic stem cell differentiation, an endogenous Wnt-mediated increase in Snail1 expression regulates neuroectodermal fate and is required for epiblast stem cell exit and mesoderm commitment, independently of EMT.\",\n      \"method\": \"Isogenic pairs of conditional knockout mouse ESCs, transcriptome analysis, differentiation assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, transcriptome, functional differentiation assays, single lab\",\n      \"pmids\": [\"24401905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Snail can potentiate transcriptional activation (in addition to repression) by collaborating with Twist at co-occupied enhancers in the mesoderm; an enriched cis-regulatory motif distinct from E-boxes was identified as essential for enhancer activation.\",\n      \"method\": \"In vivo occupancy mapping (ChIP), expression profiling of staged snail mutant embryos, in vitro enhancer activation assay, in vivo enhancer reporter assay, machine learning motif analysis, in silico mutagenesis\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, in vivo and in vitro enhancer assays, mutagenesis, expression profiling in null mutants, multiple orthogonal methods\",\n      \"pmids\": [\"24402316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MACC1 directly binds to SNAI1 protein and upregulates SNAI1 transcriptional activity, leading to transactivation of FN1 and trans-repression of CDH1, driving EMT and pancreatic cancer metastasis in a MET-independent manner.\",\n      \"method\": \"Co-IP, reporter gene assay, MACC1 overexpression/knockdown, liver metastasis mouse model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, in vivo liver metastasis model, single lab\",\n      \"pmids\": [\"36333284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STK39 (a serine/threonine kinase) interacts with and phosphorylates SNAI1 at T203, promoting SNAI1 nuclear retention and stability; STK39 inhibition destabilizes SNAI1, impairs EMT, and reduces metastasis.\",\n      \"method\": \"Co-IP, in vitro kinase assay, phosphorylation site mutagenesis, knockdown/overexpression, in vitro invasion assay, in vivo metastasis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro kinase assay, site mutagenesis, in vivo validation, single lab\",\n      \"pmids\": [\"34335956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ribotoxic stress activates JNK, which activates USP36, leading to USP36-mediated stabilization of Snail1 in the nucleolus; nucleolar Snail1 facilitates ribosome biogenesis and solid tumor cell survival, conferring resistance to homoharringtonine (HHT).\",\n      \"method\": \"JNK inhibition, USP36 knockdown, nucleolar fractionation, ribosome biogenesis assay, Co-IP, in vivo tumor model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis (JNK-USP36-Snail1), subcellular fractionation, in vivo validation, single lab\",\n      \"pmids\": [\"37833415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP9X deubiquitinates and stabilizes Snail1 protein; depletion or pharmacological inhibition of USP9X downregulates Snail1, inhibits cell migration, invasion, and metastasis, and sensitizes triple-negative breast cancer cells to cisplatin and paclitaxel.\",\n      \"method\": \"Co-IP, deubiquitination assay, knockdown/inhibitor, rescue with Snail1 overexpression, in vitro invasion assay, in vivo metastasis model\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay, Co-IP, rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"35506169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP18 deubiquitinates and stabilizes Snail1 protein in colorectal cancer; USP18 interacts with Snail1, and its overexpression promotes proliferation, migration, and invasion that is reversed by Snail1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, rescue experiment\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue, single lab\",\n      \"pmids\": [\"32742193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP22 deubiquitinates and stabilizes Snail1 protein in renal tubular epithelial cells; USP22 depletion reduces Snail1 levels, inhibits EMT, and improves renal pathology in diabetic mice.\",\n      \"method\": \"Co-IP, deubiquitination assay, USP22 knockdown/overexpression, in vivo db/db diabetic mouse model\",\n      \"journal\": \"European Journal of Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay, Co-IP, in vivo diabetic model, single lab\",\n      \"pmids\": [\"37001578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM2 deubiquitinates and stabilizes Snail1 protein in lung adenocarcinoma; TRIM2 interacts with Snail1 via Co-IP and regulates Snail1 ubiquitination-dependent degradation to promote proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"32536816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"During chondrogenesis, endogenous SNAI1 and SNAI2 proteins bind to E2-box sequences in both their own and each other's promoters, providing a molecular mechanism for compensatory transcriptional regulation between Snai1 and Snai2 during long bone development.\",\n      \"method\": \"ChIP in differentiating ATDC5 cells, conditional double knockout mouse model\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with endogenous proteins, genetic epistasis via double KO, single lab\",\n      \"pmids\": [\"23665016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GBS and other meningeal pathogens induce Snail1 expression in human brain microvascular endothelial cells via ERK1/2/MAPK signaling and bacterial cell wall components; Snail1 then represses tight junction genes (ZO-1, claudin 5, occludin) at the transcriptional level, facilitating blood-brain barrier disruption and bacterial penetration.\",\n      \"method\": \"Snail1 knockdown/overexpression, dominant-negative Snail1 in zebrafish, ERK1/2 inhibition, tight junction mRNA/protein measurement\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown, dominant-negative, in vivo zebrafish model, pathway epistasis, multiple orthogonal assays\",\n      \"pmids\": [\"25961453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The transcription factor scleraxis directly binds E-box sequences in the Snai1 promoter to transactivate Snai1 gene expression; TGFβ-mediated upregulation of Snai1 is completely dependent on scleraxis.\",\n      \"method\": \"ChIP, promoter-reporter assay, scleraxis knockdown/overexpression, epistasis with TGFβ signaling\",\n      \"journal\": \"American Journal of Physiology. Heart and Circulatory Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, epistasis, single lab\",\n      \"pmids\": [\"29906225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Snail1 and Snail2 directly repress vitamin D receptor (VDR) gene promoter activity; this repression is specific to the Snail family, as other EMT-inducing transcription factors do not affect VDR expression in colon cancer cells.\",\n      \"method\": \"Promoter-reporter assay, overexpression in colon cancer cells, specificity comparison across EMT transcription factors\",\n      \"journal\": \"The Journal of Steroid Biochemistry and Molecular Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay only, no ChIP or mutagenesis, single lab\",\n      \"pmids\": [\"20138990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNAI1 represses SNAI2 transcription by binding to E-box sequences in the SNAI2 promoter and recruiting HDAC1 to mediate histone deacetylation.\",\n      \"method\": \"ChIP, HDAC inhibitor assay, overexpression, luciferase reporter\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, histone modification assay, reporter, single lab\",\n      \"pmids\": [\"31165775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Transient (but not continuous) SNAIL1 expression in breast cancer primary tumors is sufficient and required to increase metastasis in immunocompetent mouse models; SNAIL1 gene deletion before or after tumor formation blunts metastasis.\",\n      \"method\": \"Genetic SNAIL1 reporter-transgene model, inducible SNAIL1 expression/deletion, multiple immunocompetent breast cancer mouse models\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model, inducible transgene, multiple mouse models, direct mechanistic insight into temporal requirement\",\n      \"pmids\": [\"25164016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acetate promotes SNAI1 expression under glucose limitation via ACSS2-mediated histone H3K27 acetylation at the SNAI1 regulatory region; ACSS2 knockdown abolishes acetate-induced SNAI1 upregulation and cell migration.\",\n      \"method\": \"ChIP, siRNA knockdown, overexpression, qRT-PCR, migration assay\",\n      \"journal\": \"Bioscience Reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and knockdown in single lab, limited orthogonal validation\",\n      \"pmids\": [\"32458971\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNAI1 (Snail1) is a zinc-finger transcriptional repressor and context-dependent activator that drives epithelial-mesenchymal transition primarily by recruiting epigenetic co-repressor complexes (LSD1/HDAC1, G9a/DNMTs, HDAC1/2, SETDB1) to E-box elements at target promoters (CDH1, SNAI2, ATGL, FASN, VDR, tight junction genes); its protein stability and nuclear retention are tightly regulated by a network of kinases (ERK2 downstream of DDR2/Src/ROCK, Lats2, aPKC, STK39, CK2/GSK3β) that phosphorylate specific residues to control nuclear localization and ubiquitin-mediated degradation, as well as by multiple deubiquitinases (USP27X, USP9X, USP18, USP22, USP36, TRIM2) that stabilize it; Snail1 is subject to additional post-translational modifications including poly(ADP-ribosyl)ation by PARP-1 and lactylation by CBP/p300; its mRNA stability is regulated by HuR/UDP-glucose; beyond EMT, Snail1 regulates intestinal stem cell maintenance, neuroectodermal fate in ESCs, telomere integrity, lipid metabolism in liver and adipose tissue, ribosome biogenesis under ribotoxic stress, and blood-brain barrier integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNAI1 (Snail1) is a SNAG-domain zinc-finger transcription factor that acts principally as a sequence-specific transcriptional repressor at E-box elements and is the central effector of epithelial-mesenchymal transition (EMT) [#0, #16]. Repression is achieved by recruiting epigenetic co-repressor machinery to target promoters: Snail1 binds G9a and DNA methyltransferases to deposit H3K9me2 and DNA methylation at the E-cadherin promoter [#0], and engages HDAC1/2 to deacetylate histones at the SNAI2, FASN, and other loci [#18, #23]. Through these activities Snail1 controls a broad target program — silencing CDH1, tight-junction genes (ZO-1, claudin 5, occludin), VDR, telomerase (TERT/TERRA), and lipid-handling genes (FASN, ATGL) — and can also potentiate transcriptional activation when partnered at co-occupied enhancers [#27, #36, #19, #23, #24]. Snail1 additionally autoregulates and cross-regulates within the Snail family, repressing its own and SNAI2 promoters through E-box binding [#2, #35, #39]. Snail1 abundance and nuclear retention are governed by an extensive post-translational network: phosphorylation by ERK2 (downstream of DDR2/Src and ECM stiffness/ROCK), Lats2 and STK39 at T203, and aPKC at S249 dictates nuclear accumulation versus FBXL5/CK2-GSK3β-driven ubiquitination and degradation [#1, #3, #29, #6, #5, #17, #22], while a panel of deubiquitinases (USP27X, USP9X, USP18, USP22, USP36) and PARP-1-mediated poly(ADP-ribosyl)ation stabilize the protein [#7, #31, #32, #33, #30, #4]. Upstream, Snail1 transcription is induced by TGFβ/Smad cooperating with HMGA2, by HIF-1α/2α under hypoxia, and by lactate/acetate-driven chromatin modification, and its mRNA stability is set by HuR sensing of UDP-glucose [#9, #14, #12, #41, #8]. Beyond EMT and metastasis [#40, #21], Snail1 is required for intestinal stem cell maintenance and lineage choice, neuroectodermal fate during ESC differentiation, hepatic and adipocyte lipid metabolism, nucleolar ribosome biogenesis under ribotoxic stress, and blood-brain barrier integrity [#25, #26, #23, #24, #30, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that Snail functions as a direct, sequence-specific transcriptional repressor whose activity depends on its N-terminal SNAG domain, defining its core molecular mechanism beyond E-cadherin.\",\n      \"evidence\": \"Yeast one-hybrid, EMSA with mutagenesis, and SNAG-domain mutant reporter assays at the aromatase promoter\",\n      \"pmids\": [\"11245431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the co-repressors recruited via the SNAG domain\", \"Single target gene context\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed Snail1 negatively autoregulates its own promoter, revealing a feedback loop that bounds Snail1 levels.\",\n      \"evidence\": \"ChIP, promoter-reporter assays, and E-box mutagenesis\",\n      \"pmids\": [\"16617148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative impact of the loop on EMT dynamics not defined\", \"Co-repressors at the autoregulated promoter not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the epigenetic effectors of Snail1 repression, linking it to histone H3K9 methylation and DNA methylation at the E-cadherin promoter.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, and knockdown across EMT models showing G9a/DNMT recruitment\",\n      \"pmids\": [\"22406531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether G9a/DNMT recruitment generalizes to all Snail1 targets unknown\", \"Order of H3K9me2 versus DNA methylation deposition not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined how kinase signaling controls Snail1 nuclear retention and stability, with Lats2 phosphorylation at T203 promoting nuclear retention and EMT activity.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, T203 mutagenesis, and in vivo zebrafish/mouse models\",\n      \"pmids\": [\"21952048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same T203 site integrates inputs from other kinases not addressed\", \"Relationship to nuclear export machinery unresolved at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected extracellular collagen sensing to Snail1 stabilization, showing DDR2-Src-ERK2 directly phosphorylates Snail1 to extend its half-life and drive metastasis.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mapping, ubiquitylation assays, and in vivo metastasis models\",\n      \"pmids\": [\"23644467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise ERK2 phosphosite-to-ubiquitin-machinery link not fully mapped\", \"Crosstalk with degradative kinases not integrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified FBXL5 as the nuclear E3 ligase that ubiquitinates Snail1 and impairs its DNA binding, and clarified that Lats2 phosphorylation blocks export but not ubiquitination.\",\n      \"evidence\": \"shRNA screen, Co-IP, ubiquitination and DNA-binding assays, subcellular fractionation, epistasis with Lats2\",\n      \"pmids\": [\"24157836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cytosolic degradation uses a distinct ligase unresolved\", \"Stoichiometry of phosphorylation versus ubiquitination not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked epithelial polarity to Snail1 turnover, showing aPKC phosphorylation at S249 degrades Snail1 when polarity is intact, and loss of polarity stabilizes it to license EMT.\",\n      \"evidence\": \"3D organoids, S249 mutagenesis, PAR-complex loss-of-function, xenografts, human tissue correlation\",\n      \"pmids\": [\"30804505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligase coupled to S249 phosphorylation not identified\", \"Interplay between S249 and T203 phosphorylation not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established deubiquitination as a major Snail1-stabilizing mechanism, with USP27X required for TGFβ-induced Snail1 expression and metastasis.\",\n      \"evidence\": \"siRNA screen, Co-IP, deubiquitination assay, and in vitro/in vivo invasion-metastasis assays\",\n      \"pmids\": [\"30341066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity among multiple Snail1 DUBs not compared\", \"Lysine residues targeted not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the temporal requirement for Snail1 in metastasis, showing transient rather than continuous expression is sufficient and required to promote dissemination.\",\n      \"evidence\": \"Inducible SNAIL1 reporter-transgene and deletion in multiple immunocompetent breast cancer mouse models\",\n      \"pmids\": [\"25164016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular memory underlying transient-expression sufficiency not defined\", \"Cell-of-origin dependence not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded Snail1 biology beyond cancer, establishing essential roles in intestinal stem cell maintenance, lineage choice, and damage response.\",\n      \"evidence\": \"Conditional intestinal Snai1 knockout, organoids, lineage tracing, and in vivo radiation model\",\n      \"pmids\": [\"25759216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes mediating stem cell survival not identified\", \"Relationship to EMT program in this context unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed non-EMT metabolic functions, showing Snail1 represses lipogenic and lipolytic genes (FASN, ATGL) via HDAC recruitment to control tissue lipid balance.\",\n      \"evidence\": \"ChIP, tissue-specific conditional knockouts, promoter-reporter assays, and metabolic phenotyping\",\n      \"pmids\": [\"30013137\", \"27851965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that direct Snail1 to metabolic versus EMT promoters unknown\", \"How insulin/non-canonical input couples to Snail1 not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified lactylation as a metabolic post-translational mark on Snail1, with CBP/p300-mediated lactylation driving endothelial transition and EMT downstream of glycolysis.\",\n      \"evidence\": \"Co-IP, lactylation assays, MCT inhibition, and in vivo myocardial infarction and xenograft models\",\n      \"pmids\": [\"36735787\", \"39462429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylated residues not definitively mapped\", \"Functional interplay with phosphorylation/ubiquitination not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a nucleolar role for Snail1 in ribosome biogenesis under stress, with JNK-USP36 stabilizing nucleolar Snail1 to support tumor cell survival.\",\n      \"evidence\": \"JNK inhibition, USP36 knockdown, nucleolar fractionation, ribosome biogenesis assays, and in vivo tumor model\",\n      \"pmids\": [\"37833415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct nucleolar targets/mechanism of ribosome biogenesis support unknown\", \"Whether DNA/E-box binding is involved nucleolarly unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dense network of competing kinases, ligases, deubiquitinases, and metabolic PTMs is integrated to set Snail1 dosage, residence, and target selectivity in a given tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of Snail1 PTM hierarchy\", \"Determinants of repressor versus activator/enhancer behavior not defined\", \"Context-specific target gene selection mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 16, 18, 23, 24, 27]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 16, 19, 35]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 5, 6, 29]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 16, 18, 23, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 26, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 14, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 7, 6, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [40, 21, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"G9a\", \"Lats2\", \"STK39\", \"FBXL5\", \"USP27X\", \"HMGA2\", \"PARP-1\", \"HDAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}