{"gene":"ST3GAL1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2020,"finding":"ST3GAL1 is transcriptionally induced by the SOX2-GLI1 oncogenic complex in melanoma. ST3GAL1 drives melanoma metastasis by sialylating the receptor tyrosine kinase AXL, inducing AXL dimerization and activation, which in turn promotes melanoma invasion.","method":"In vitro and in vivo silencing experiments, glycosylated protein analysis, co-IP/pulldown to identify AXL as substrate, functional invasion and metastasis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional validation in vitro and in vivo, substrate identification by glycoprotein analysis, mechanistic pathway (SOX2-GLI1→ST3GAL1→AXL dimerization→invasion) supported by multiple orthogonal methods in one study","pmids":["33203881"],"is_preprint":false},{"year":2019,"finding":"ST3GAL1 sialylates vasorin (VASN) on O-glycans (predominantly sialyl-3T and disialyl-T structures). Sialylation of VASN by ST3GAL1 reduces VASN binding to TGF-β1 by 2–3-fold; desialylation or ST3GAL1 silencing enhances VASN–TGF-β1 binding, dampening TGF-β1/Smad2/Smad3 signaling and tumor angiogenesis. TGF-β1 in turn transcriptionally activates ST3GAL1, forming a feedback loop.","method":"LC-MS/MS O-glycan profiling of secreted VASN, ST3GAL1 siRNA knockdown, neuraminidase desialylation, HUVEC tube formation assay, Smad2/Smad3 phosphorylation assay, MCF7 xenograft model","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structural O-glycan characterization by LC-MS/MS combined with functional in vitro and in vivo assays and mechanistic signaling readouts, single lab but multiple orthogonal methods","pmids":["30252131"],"is_preprint":false},{"year":2020,"finding":"ST3GAL1 mediates O-linked sialylation of CD55, shifting its O-glycan profile toward disialylated core 2 structures. This sialylation of CD55 reduces C3 deposition, protecting breast cancer cells from complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity, thereby enabling immune evasion.","method":"ST3GAL1 siRNA knockdown, tandem mass spectrometry of N- and O-glycans from CD55, C3 deposition assay, complement-mediated lysis assay, ADCC assay","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structural glycan analysis by MS combined with functional immune cytotoxicity assays, multiple orthogonal methods in one study identifying specific O-glycan substrate and functional consequence","pmids":["33177111"],"is_preprint":false},{"year":2023,"finding":"ST3GAL1 glycosylates CD18 (integrin β2) in activated CD8+ T cells, inducing spontaneous nonspecific tissue sequestration of T cells by altering LFA-1 endocytic recycling. This impairs cancer-specific migration of CAR T cells. βII-spectrin, a cytoskeletal LFA-1-associated molecule, reverses ST3GAL1-mediated nonspecific migration.","method":"In vivo CRISPR-Cas9 pooled loss-of-function screen, glycosylated protein analysis identifying CD18 as substrate, LFA-1 endocytic recycling assays, engineered CAR T cells with βII-spectrin overexpression, in vivo tumor models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR screen plus mechanistic substrate identification plus functional rescue with βII-spectrin, multiple orthogonal methods, peer-reviewed","pmids":["37069398"],"is_preprint":false},{"year":2018,"finding":"ST3GAL1 mediates O-linked sialylation of GFRA1, which is required for GDNF-induced RET, AKT, and ERα phosphorylation in ER-positive breast cancer cells. ST3GAL1 silencing reduces GDNF-mediated signaling and cell proliferation. GDNF transcriptionally induces ST3GAL1, forming a positive feedback loop.","method":"ST3GAL1 siRNA knockdown, phosphorylation assays (RET, AKT, ERα), identification of GFRA1 as O-sialylation substrate, GDNF stimulation assays, cell proliferation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification with functional signaling readouts, single lab, multiple pathway readouts but no structural/MS glycan validation explicitly described in abstract","pmids":["30040982"],"is_preprint":false},{"year":2020,"finding":"ST3GAL1 modulates EGFR sialylation to inhibit EGFR phosphorylation in renal cell carcinoma cells, affecting activation of the PI3K-AKT pathway. ST3GAL1 transcription is regulated by c-Jun (JUN), which binds the ST3GAL1 promoter; the lncRNA MEG3 controls c-Jun expression, thereby regulating ST3GAL1.","method":"Bioinformatics identification of c-Jun as ST3GAL1 promoter-binding transcription factor, MEG3 overexpression/knockdown, EGFR phosphorylation and PI3K-AKT pathway assays in RCC cells, in vivo xenograft","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional epistasis via MEG3→c-Jun→ST3GAL1→EGFR sialylation→PI3K-AKT, multiple readouts but mechanism of EGFR sialylation not structurally characterized in abstract","pmids":["32737220"],"is_preprint":false},{"year":2016,"finding":"Active recombinant human ST3GAL1 was expressed in E. coli and shown to catalyze transfer of sialic acid to galactoside substrates including lactose, N-acetyllactosamine, and benzyl 2-acetamido-2-deoxy-3-O-(β-d-galactopyranosyl)-α-d-galactopyranoside, confirming its enzymatic activity on type III disaccharides (Galβ1,3GalNAc).","method":"Recombinant protein expression in E. coli with solubility-enhancing fusions and disulfide bond optimization, in vitro sialylation assays on defined substrates","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic reconstitution with defined substrates, multiple expression conditions tested, rigorous biochemical study","pmids":["27166796"],"is_preprint":false},{"year":2022,"finding":"ST3GAL1 and ST3GAL2 both function as cellular O-glycan sialyltransferases acting on Galβ1,3GalNAc residues in hematopoietic and megakaryocytic cells. CD34, CD43, and GPIbα are major glycoprotein substrates shared by ST3GAL1 and ST3GAL2, while GPIIb O-sialylation relies predominantly on ST3GAL2. Loss of both ST3GAL1 and ST3GAL2 dramatically impairs megakaryocyte proplatelet formation.","method":"ST3GAL1/ST3GAL2 single and double knockout human iPSC lines, differentiation to HPCs and MKs, peanut agglutinin lectin binding assay, substrate glycoprotein identification, proplatelet formation assay","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype, substrate identification by lectin binding in defined KO backgrounds, multiple orthogonal assays in one study","pmids":["35507766"],"is_preprint":false},{"year":2018,"finding":"ST3GAL1 overexpression in ovarian cancer cells increases cell growth, migration, invasion, and paclitaxel resistance in vitro and in vivo. TGF-β1 increases ST3GAL1 expression and induces EMT; ST3GAL1 knockdown inhibits TGF-β1-induced EMT marker expression.","method":"ST3GAL1 overexpression/knockdown in ovarian cancer cell lines, paclitaxel resistance assays in vitro and in mouse xenograft, TGF-β1 stimulation with EMT marker western blotting","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss- and gain-of-function with in vivo validation, TGF-β1 pathway linkage, but molecular substrate of sialylation not identified","pmids":["30375371"],"is_preprint":false},{"year":2024,"finding":"ST3GAL1 synthesizes sialoglycans capable of engaging the Siglec-7 and Siglec-9 immunoreceptors on immune cells, enabling prostate cancer immune evasion. ST3GAL1 levels inversely correlate with androgen signaling in prostate tumors.","method":"ST3GAL1 expression analysis in prostate tumor specimens, Siglec-7/9 ligand detection, functional immune evasion assays, modulation by enzalutamide","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Siglec-7/9 ligand identification linked to ST3GAL1 activity with functional immune readouts; single lab","pmids":["38448753"],"is_preprint":false},{"year":2025,"finding":"ST3GAL1 sialylates neuropilin-1 (NRP1), and this sialylation increases NRP1 binding affinity toward EGFR at the molecular level. ST3GAL1 silencing impairs cell migration and wound healing linked to reduced CAPN2 activity as a consequence of diminished EGF/EGFR signaling. ST3GAL1 silencing also augments sensitivity to cetuximab-mediated cell lysis.","method":"Identification of NRP1 as ST3GAL1 substrate, co-IP/binding affinity assays between NRP1 and EGFR, ST3GAL1 siRNA knockdown, migration/wound healing assays, CAPN2 activity assay, cetuximab cytotoxicity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification with molecular binding affinity measurement and functional downstream signaling readouts, single lab","pmids":["40024474"],"is_preprint":false},{"year":2026,"finding":"RANKL activates c-FOS to drive ST3GAL1 transcription in osteoclasts, promoting osteoclastogenesis. Estrogen-bound ERα competes with TRAF6 and suppresses this c-FOS-dependent ST3GAL1 induction. In vivo sialidase treatment in estrogen-deficient models reduces osteoclast-mediated bone loss, mimicking estradiol effects.","method":"Transcriptional pathway analysis (c-FOS/ST3GAL1), ERα-TRAF6 competition assay, single-cell RNA sequencing of human bone, in vivo sialidase treatment in estrogen-deficient mouse models, serum sialic acid measurement in clinical cohort","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic transcriptional pathway established (RANKL→c-FOS→ST3GAL1) with ERα suppression mechanism and in vivo sialidase rescue, single study","pmids":["41680135"],"is_preprint":false},{"year":2026,"finding":"NRF2 directly binds to two key regions on the ST3GAL1 promoter (−1107~−771 and −437~+195) to enhance ST3GAL1 transcription in colorectal cancer. ST3GAL1 mediates sialylation of integrin-α6β4 at specific O-glycosylation sites (ITGA6: S934, S937, T944; ITGB4: S1515, S1517, T1524), thereby activating downstream FAK/SRC signaling and promoting metastasis. Catalytic-domain mutant ST3GAL1 (H299A) has no tumor-promoting effect, confirming dependence on sialyltransferase activity.","method":"Dual luciferase mutation assay and ChIP-qPCR for NRF2-ST3GAL1 promoter interaction, lectin affinity immunoprecipitation, site-directed mutagenesis of O-glycosylation sites on integrin-α6β4, catalytic dead mutant (H299A), FAK/SRC phosphorylation assays, in vivo xenograft models","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — catalytic mutagenesis (H299A) confirms enzyme activity requirement, site-directed mutagenesis identifies specific substrate O-glycosylation sites, ChIP-qPCR and luciferase validate transcriptional regulation; multiple orthogonal methods in single study","pmids":["41904587"],"is_preprint":false},{"year":2025,"finding":"ST3GAL1 directly binds MUCL1 and catalyzes its sialylation, increasing MUCL1 protein stability and promoting breast cancer cell proliferation, migration, invasion, and in vivo tumor growth and lung metastasis. These effects are reversed by sialyltransferase inhibitor Lith-O-Asp or MUCL1 knockdown.","method":"Co-IP demonstrating ST3GAL1-MUCL1 direct binding, sialylation assay, ST3GAL1 knockdown/overexpression, MUCL1 stability assay, Lith-O-Asp inhibitor treatment, in vivo tumor and metastasis models","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification by Co-IP, functional rescue with inhibitor and MUCL1 KD, in vivo validation; single lab","pmids":["41770470"],"is_preprint":false},{"year":2025,"finding":"ST3GAL1 directly glycosylates VEGF-A (confirmed by Duolink proximity ligation assay and co-immunoprecipitation) and activates FAK/paxillin signaling, promoting VEGF-A expression and EMT in endometrial cancer. ST3GAL1 inhibition with soyasaponin I (SsaI) reduces VEGF-A signaling and synergizes with bevacizumab in vivo.","method":"Duolink proximity ligation assay, co-immunoprecipitation, ST3GAL1 knockdown, SsaI pharmacological inhibition, in vitro migration/invasion assays, in vivo xenograft with bevacizumab combination","journal":"International journal of gynaecology and obstetrics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate interaction confirmed by two proximity methods (PLA + co-IP), FAK/paxillin pathway readout, in vivo validation; single lab","pmids":["40497576"],"is_preprint":false},{"year":2026,"finding":"ST3GAL1 knockdown significantly reduces Siglec-7 ligand expression on liver cancer cells (HCC), enhancing susceptibility to NK cell-mediated cytotoxicity and cetuximab-induced ADCC. Sorafenib-resistant HCC cells display hypersialylation with increased Siglec-7/9 ligands, conferring NK cell evasion that is reversed by ST3GAL1 silencing.","method":"ST3GAL1 siRNA knockdown, Siglec-7/9 ligand surface staining, NK cell cytotoxicity assays, ADCC assay, sorafenib-resistant cell lines","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional immune cytotoxicity assays with defined ST3GAL1 loss-of-function, ligand profiling; single lab","pmids":["41961075"],"is_preprint":false},{"year":2024,"finding":"A universal glycosyltransferase continuous (UGC) assay revealed that ST3GAL1 inhibition by soyasaponin-1 is time-dependent, and ST3GAL1 is the most responsive of three tested glycosyltransferases (IC50 ~37 µM vs. 52 µM for FUT1 and 886 µM for C1GALT1). The kinetic parameters (Km) of ST3GAL1 were standardized using CMP as nucleotide donor.","method":"Continuous fluorometric glycosyltransferase assay (UGC), kinetic parameter determination, dose-response inhibition with soyasaponin-1","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro enzymatic kinetics assay with defined inhibitor, but single lab and primarily a methods development study; IC50 values provided","pmids":["38645360"],"is_preprint":false},{"year":2025,"finding":"Androgen-androgen receptor (AR) signaling in the submandibular gland negatively regulates ST3GAL1 (and ST3GAL4), reducing MUC10 sialylation. This correlates with sex differences in oral microbiota composition, as female-preferring bacteria such as Akkermansia muciniphila can assimilate mucin by degrading terminal sialic acids.","method":"Neuraminidase treatment showing sialic acid contribution to MUC10 mobility on SDS-PAGE, androgen manipulation experiments, RT-PCR for ST3GAL1 expression, microbiota profiling","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — AR signaling linkage to ST3GAL1 expression shown, MUC10 sialylation role inferred from neuraminidase experiment; functional consequence in microbiota is correlative; single lab, limited mechanistic detail","pmids":["39572079"],"is_preprint":false},{"year":2025,"finding":"AR and MYC cooperatively repress ST3GAL1 transcription in prostate cancer cells, limiting synthesis of Siglec-7 ligands. Supraphysiological androgen levels produce distinct glycopeptide profiles compared with physiological androgen levels, with O-glycans as major substrates for sialylation in prostate cancer.","method":"AR and MYC manipulation in prostate cancer cells, glycopeptide profiling, Siglec-7 ligand quantification, transcriptional regulation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — preprint, single lab, mechanistic detail in abstract is limited; cooperative AR/MYC repression of ST3GAL1 shown but not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2018,"finding":"ST3GAL1 overexpression in bladder cancer cells (converting T antigen to sialyl-T antigen) increases sensitivity to oxidative damage and modulates the transcriptome toward genomic instability. BCG challenge of ST3GAL1-overexpressing cells induces stronger macrophage secretion of IL-6, IL-1β, TNFα, and IL-10 compared to T-antigen-expressing cells.","method":"Retroviral transduction of ST3GAL1 cDNA into bladder cancer cells, whole-genome microarray, multiplex cytokine immunoassay of macrophage secretome, BCG challenge assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ST3GAL1 expression manipulation with defined T→sialyl-T conversion, transcriptomic and cytokine functional readouts; multiple methods in single study","pmids":["29454317"],"is_preprint":false}],"current_model":"ST3GAL1 is a type II transmembrane sialyltransferase that catalyzes the transfer of sialic acid in α2,3-linkage to Galβ1,3GalNAc (core 1 O-glycan) residues on diverse glycoprotein substrates including CD55, CD18/LFA-1, vasorin, GFRA1, NRP1, AXL, GPIbα, CD34, CD43, integrin-α6β4, VEGF-A, and MUCL1; this substrate sialylation modulates receptor dimerization and signaling (AXL, EGFR/NRP1, VEGF-R2, FAK/SRC, PI3K-AKT), complement evasion (CD55), immune checkpoint engagement (Siglec-7/9 via sialoglycans), and T cell trafficking (LFA-1 endocytic recycling via CD18), while its transcription is regulated by TGF-β1, GDNF, SOX2-GLI1, NRF2, c-FOS/RANKL, and androgen-AR signaling."},"narrative":{"mechanistic_narrative":"ST3GAL1 is a sialyltransferase that transfers sialic acid in α2,3-linkage onto the Galβ1,3GalNAc (core 1 / T-antigen) disaccharide of O-glycans, an activity reconstituted with recombinant enzyme on defined galactoside substrates and dependent on an intact catalytic domain (H299A mutant is inactive and non-tumorigenic) [PMID:27166796, PMID:41904587]. Through this O-glycan sialylation it remodels the glycocalyx of numerous cell-surface and secreted proteins to tune receptor signaling, complement and immune evasion, and cell migration. It sialylates receptor tyrosine kinase pathway components to promote oncogenic signaling: AXL (driving dimerization and melanoma invasion) [PMID:33203881], GFRA1 (enabling GDNF-induced RET/AKT/ERα phosphorylation) [PMID:30040982], neuropilin-1 (increasing NRP1–EGFR binding affinity and EGF/EGFR-driven migration) [PMID:40024474], and integrin-α6β4 at defined O-glycosylation sites to activate FAK/SRC and metastasis [PMID:41904587]; it also sialylates VEGF-A to drive FAK/paxillin signaling and EMT [PMID:40497576] and stabilizes MUCL1 to promote proliferation and metastasis [PMID:41770470]. ST3GAL1-dependent sialoglycans engage the inhibitory immunoreceptors Siglec-7 and Siglec-9 to evade NK- and complement-mediated killing across prostate, liver, and breast cancers, including sialylation of CD55 that reduces C3 deposition [PMID:33177111, PMID:38448753, PMID:41961075]. In immune and hematopoietic cells it sialylates CD18 to alter LFA-1 endocytic recycling and T-cell trafficking [PMID:37069398] and, redundantly with ST3GAL2, sialylates CD34, CD43, and GPIbα to support megakaryocyte proplatelet formation [PMID:35507766]. ST3GAL1 transcription is controlled by multiple inducers and repressors including SOX2-GLI1, TGF-β1, GDNF, NRF2, and RANKL/c-FOS, with androgen-AR and estrogen-ERα signaling acting as negative regulators [PMID:33203881, PMID:30252131, PMID:41680135, PMID:41904587].","teleology":[{"year":2016,"claim":"Establishing that human ST3GAL1 is itself a catalytically active enzyme on the core 1 disaccharide grounded all later substrate-specific claims in a defined biochemical activity.","evidence":"Recombinant human ST3GAL1 expressed in E. coli, in vitro sialylation assays on lactose, LacNAc, and Galβ1,3GalNAc substrates","pmids":["27166796"],"confidence":"High","gaps":["No structural model of the catalytic or transmembrane domain","Donor/acceptor kinetics on native glycoprotein substrates not addressed"]},{"year":2018,"claim":"Linked ST3GAL1 to receptor-mediated growth signaling and to cytokine/oxidative phenotypes, moving it from an enzyme to a driver of cancer cell behavior.","evidence":"siRNA knockdown with GFRA1 substrate identification and RET/AKT/ERα phosphorylation readouts in breast cancer; retroviral overexpression in bladder cancer with transcriptomic and macrophage cytokine profiling","pmids":["30040982","29454317"],"confidence":"Medium","gaps":["GFRA1 O-glycan structures not characterized by MS","Mechanism linking sialyl-T conversion to oxidative sensitivity unresolved"]},{"year":2019,"claim":"Showed ST3GAL1 sialylation can dampen rather than promote signaling, and identified a TGF-β1 feedback loop, refining the model of how it tunes pathways.","evidence":"LC-MS/MS O-glycan profiling of secreted vasorin, neuraminidase desialylation, Smad2/3 phosphorylation and HUVEC tube formation assays, MCF7 xenograft","pmids":["30252131"],"confidence":"High","gaps":["Whether the same VASN sialoforms operate in vivo across tumor types not tested","Stoichiometry of VASN sialylation versus TGF-β1 binding not quantified"]},{"year":2020,"claim":"Defined ST3GAL1 as an oncogenic transcriptional target and a node controlling immune evasion and receptor activation through distinct substrates.","evidence":"SOX2-GLI1-induced ST3GAL1 with AXL substrate identification and metastasis assays (melanoma); CD55 O-glycan MS with C3 deposition/complement/ADCC assays (breast); MEG3→c-Jun→ST3GAL1 axis with EGFR sialylation and PI3K-AKT readouts (RCC)","pmids":["33203881","33177111","32737220"],"confidence":"High","gaps":["Direct sialylation site mapping on AXL and EGFR not resolved","Context-dependent opposite effects on EGFR versus other RTKs unexplained"]},{"year":2022,"claim":"Genetic dissection in iPSC-derived cells showed ST3GAL1 acts redundantly with ST3GAL2 on shared core 1 substrates required for blood cell function.","evidence":"ST3GAL1/ST3GAL2 single and double knockout iPSC lines, PNA lectin binding, substrate identification, proplatelet formation assays","pmids":["35507766"],"confidence":"High","gaps":["Relative contribution of each enzyme per substrate not fully partitioned","Physiological platelet phenotype in vivo not established"]},{"year":2023,"claim":"Identified CD18 as a substrate whose sialylation misroutes T-cell trafficking, establishing ST3GAL1 as a barrier to adoptive cell therapy with a defined rescue.","evidence":"In vivo CRISPR-Cas9 loss-of-function screen, CD18 substrate identification, LFA-1 endocytic recycling assays, βII-spectrin overexpression rescue in CAR T cells","pmids":["37069398"],"confidence":"High","gaps":["Molecular link between CD18 sialylation and recycling machinery incompletely defined","Generalizability across T-cell subsets not established"]},{"year":2024,"claim":"Connected ST3GAL1 to Siglec-7/9 ligand synthesis as a mechanism of cancer immune evasion and provided standardized inhibitor kinetics.","evidence":"Siglec-7/9 ligand detection and immune evasion assays in prostate cancer with enzalutamide modulation; UGC fluorometric kinetic assay with soyasaponin-1 IC50 determination","pmids":["38448753","38645360"],"confidence":"Medium","gaps":["Specific glycoprotein carriers of Siglec ligands not identified","Inhibitor selectivity in cells beyond in vitro kinetics untested"]},{"year":2025,"claim":"Extended the substrate repertoire (NRP1, VEGF-A, MUCL1) and reinforced the Siglec-mediated immune evasion model while implicating ST3GAL1 in therapy resistance.","evidence":"Co-IP/PLA substrate confirmation and binding affinity assays for NRP1-EGFR, VEGF-A FAK/paxillin signaling with bevacizumab synergy, MUCL1 stability with Lith-O-Asp inhibitor; Siglec-7 ligand and NK/ADCC assays in sorafenib-resistant HCC","pmids":["40024474","40497576","41770470","41961075"],"confidence":"Medium","gaps":["Sialylation sites on NRP1 and VEGF-A not mapped","Whether MUCL1 stabilization is direct consequence of sialylation untested in cell-free system"]},{"year":2026,"claim":"Resolved transcriptional control nodes and proved catalytic dependence, mapping specific substrate O-glycosylation sites and linking ST3GAL1 to bone homeostasis.","evidence":"NRF2 ChIP-qPCR/luciferase promoter mapping, integrin-α6β4 site-directed mutagenesis with H299A catalytic-dead mutant and FAK/SRC readouts (CRC); RANKL→c-FOS induction, ERα-TRAF6 competition, and in vivo sialidase rescue in bone","pmids":["41904587","41680135"],"confidence":"High","gaps":["Whether bone osteoclast substrate(s) of ST3GAL1 are defined","Integration of the many transcriptional regulators in a single cell context unresolved"]},{"year":null,"claim":"It remains unresolved which structural features dictate ST3GAL1 substrate selection across its diverse glycoprotein targets and how opposing signaling outcomes (e.g., AXL/RTK activation versus EGFR inhibition) are determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis for acceptor specificity","Context-dependent pro- versus anti-signaling effects unexplained","Sialylation site maps absent for most substrates"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,7,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,12,13]}],"localization":[],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,9,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,10,12]}],"complexes":[],"partners":["AXL","VASN","CD55","CD18","GFRA1","NRP1","MUCL1","VEGFA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q11201","full_name":"CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1","aliases":["Gal-NAc6S","Gal-beta-1,3-GalNAc-alpha-2,3-sialyltransferase","Monosialoganglioside sialyltransferase","SIATFL","ST3Gal I","ST3GalI","ST3GalA.1","ST3O","Sialyltransferase 4A","SIAT4-A"],"length_aa":340,"mass_kda":39.1,"function":"A beta-galactoside alpha2->3 sialyltransferase involved in terminal sialylation of glycoproteins and glycolipids (PubMed:31784620, PubMed:8027041). Catalyzes the transfer of sialic acid (N-acetyl-neuraminic acid; Neu5Ac) from the nucleotide sugar donor CMP-Neu5Ac onto acceptor Galbeta-(1->3)-GalNAc-terminated glycoconjugates through an alpha2-3 linkage (PubMed:31784620, PubMed:8027041, PubMed:31719620). Adds sialic acid to the core 1 O-glycan, Galbeta-(1->3)-GalNAc-O-Ser/Thr, which is a major structure of mucin-type O-glycans. As part of a homeostatic mechanism that regulates CD8-positive T cell numbers, sialylates core 1 O-glycans of T cell glycoproteins, SPN/CD43 and PTPRC/CD45. Prevents premature apoptosis of thymic CD8-positive T cells prior to peripheral emigration, whereas in the secondary lymphoid organs controls the survival of CD8-positive memory T cells generated following a successful immune response (By similarity). Transfers sialic acid to asialofetuin, presumably onto Galbeta-(1->3)-GalNAc-O-Ser (By similarity). Sialylates GM1a, GA1 and GD1b gangliosides to form GD1a, GM1b and GT1b, respectively (By similarity) (PubMed:8027041)","subcellular_location":"Golgi apparatus, Golgi stack membrane; Golgi apparatus, trans-Golgi network membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q11201/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ST3GAL1","classification":"Not Classified","n_dependent_lines":101,"n_total_lines":1208,"dependency_fraction":0.0836092715231788},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ST3GAL1","total_profiled":1310},"omim":[{"mim_id":"607188","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 2; ST3GAL2","url":"https://www.omim.org/entry/607188"},{"mim_id":"607187","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 1; ST3GAL1","url":"https://www.omim.org/entry/607187"},{"mim_id":"104240","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 4; ST3GAL4","url":"https://www.omim.org/entry/104240"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ST3GAL1"},"hgnc":{"alias_symbol":["ST3O","SIATFL","ST3GalA.1"],"prev_symbol":["SIAT4A"]},"alphafold":{"accession":"Q11201","domains":[{"cath_id":"3.90.1480.20","chopping":"71-336","consensus_level":"high","plddt":95.0817,"start":71,"end":336}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q11201","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q11201-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q11201-F1-predicted_aligned_error_v6.png","plddt_mean":90.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ST3GAL1","jax_strain_url":"https://www.jax.org/strain/search?query=ST3GAL1"},"sequence":{"accession":"Q11201","fasta_url":"https://rest.uniprot.org/uniprotkb/Q11201.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q11201/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q11201"}},"corpus_meta":[{"pmid":"30375371","id":"PMC_30375371","title":"Sialyltransferase ST3GAL1 promotes cell migration, invasion, and TGF-β1-induced EMT and confers paclitaxel resistance in ovarian cancer.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30375371","citation_count":154,"is_preprint":false},{"pmid":"33203881","id":"PMC_33203881","title":"ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33203881","citation_count":78,"is_preprint":false},{"pmid":"30252131","id":"PMC_30252131","title":"Sialylation of vasorin by ST3Gal1 facilitates TGF-β1-mediated tumor angiogenesis and progression.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30252131","citation_count":60,"is_preprint":false},{"pmid":"33177111","id":"PMC_33177111","title":"Sialylation of CD55 by ST3GAL1 Facilitates Immune Evasion in Cancer.","date":"2020","source":"Cancer 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function","date":"2025-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.658684","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20735,"output_tokens":6021,"usd":0.07626,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14705,"output_tokens":3783,"usd":0.08405,"stage2_stop_reason":"end_turn"},"total_usd":0.16031,"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\": 2020,\n      \"finding\": \"ST3GAL1 is transcriptionally induced by the SOX2-GLI1 oncogenic complex in melanoma. ST3GAL1 drives melanoma metastasis by sialylating the receptor tyrosine kinase AXL, inducing AXL dimerization and activation, which in turn promotes melanoma invasion.\",\n      \"method\": \"In vitro and in vivo silencing experiments, glycosylated protein analysis, co-IP/pulldown to identify AXL as substrate, functional invasion and metastasis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional validation in vitro and in vivo, substrate identification by glycoprotein analysis, mechanistic pathway (SOX2-GLI1→ST3GAL1→AXL dimerization→invasion) supported by multiple orthogonal methods in one study\",\n      \"pmids\": [\"33203881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST3GAL1 sialylates vasorin (VASN) on O-glycans (predominantly sialyl-3T and disialyl-T structures). Sialylation of VASN by ST3GAL1 reduces VASN binding to TGF-β1 by 2–3-fold; desialylation or ST3GAL1 silencing enhances VASN–TGF-β1 binding, dampening TGF-β1/Smad2/Smad3 signaling and tumor angiogenesis. TGF-β1 in turn transcriptionally activates ST3GAL1, forming a feedback loop.\",\n      \"method\": \"LC-MS/MS O-glycan profiling of secreted VASN, ST3GAL1 siRNA knockdown, neuraminidase desialylation, HUVEC tube formation assay, Smad2/Smad3 phosphorylation assay, MCF7 xenograft model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural O-glycan characterization by LC-MS/MS combined with functional in vitro and in vivo assays and mechanistic signaling readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30252131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ST3GAL1 mediates O-linked sialylation of CD55, shifting its O-glycan profile toward disialylated core 2 structures. This sialylation of CD55 reduces C3 deposition, protecting breast cancer cells from complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity, thereby enabling immune evasion.\",\n      \"method\": \"ST3GAL1 siRNA knockdown, tandem mass spectrometry of N- and O-glycans from CD55, C3 deposition assay, complement-mediated lysis assay, ADCC assay\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural glycan analysis by MS combined with functional immune cytotoxicity assays, multiple orthogonal methods in one study identifying specific O-glycan substrate and functional consequence\",\n      \"pmids\": [\"33177111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ST3GAL1 glycosylates CD18 (integrin β2) in activated CD8+ T cells, inducing spontaneous nonspecific tissue sequestration of T cells by altering LFA-1 endocytic recycling. This impairs cancer-specific migration of CAR T cells. βII-spectrin, a cytoskeletal LFA-1-associated molecule, reverses ST3GAL1-mediated nonspecific migration.\",\n      \"method\": \"In vivo CRISPR-Cas9 pooled loss-of-function screen, glycosylated protein analysis identifying CD18 as substrate, LFA-1 endocytic recycling assays, engineered CAR T cells with βII-spectrin overexpression, in vivo tumor models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR screen plus mechanistic substrate identification plus functional rescue with βII-spectrin, multiple orthogonal methods, peer-reviewed\",\n      \"pmids\": [\"37069398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ST3GAL1 mediates O-linked sialylation of GFRA1, which is required for GDNF-induced RET, AKT, and ERα phosphorylation in ER-positive breast cancer cells. ST3GAL1 silencing reduces GDNF-mediated signaling and cell proliferation. GDNF transcriptionally induces ST3GAL1, forming a positive feedback loop.\",\n      \"method\": \"ST3GAL1 siRNA knockdown, phosphorylation assays (RET, AKT, ERα), identification of GFRA1 as O-sialylation substrate, GDNF stimulation assays, cell proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification with functional signaling readouts, single lab, multiple pathway readouts but no structural/MS glycan validation explicitly described in abstract\",\n      \"pmids\": [\"30040982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ST3GAL1 modulates EGFR sialylation to inhibit EGFR phosphorylation in renal cell carcinoma cells, affecting activation of the PI3K-AKT pathway. ST3GAL1 transcription is regulated by c-Jun (JUN), which binds the ST3GAL1 promoter; the lncRNA MEG3 controls c-Jun expression, thereby regulating ST3GAL1.\",\n      \"method\": \"Bioinformatics identification of c-Jun as ST3GAL1 promoter-binding transcription factor, MEG3 overexpression/knockdown, EGFR phosphorylation and PI3K-AKT pathway assays in RCC cells, in vivo xenograft\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional epistasis via MEG3→c-Jun→ST3GAL1→EGFR sialylation→PI3K-AKT, multiple readouts but mechanism of EGFR sialylation not structurally characterized in abstract\",\n      \"pmids\": [\"32737220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Active recombinant human ST3GAL1 was expressed in E. coli and shown to catalyze transfer of sialic acid to galactoside substrates including lactose, N-acetyllactosamine, and benzyl 2-acetamido-2-deoxy-3-O-(β-d-galactopyranosyl)-α-d-galactopyranoside, confirming its enzymatic activity on type III disaccharides (Galβ1,3GalNAc).\",\n      \"method\": \"Recombinant protein expression in E. coli with solubility-enhancing fusions and disulfide bond optimization, in vitro sialylation assays on defined substrates\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic reconstitution with defined substrates, multiple expression conditions tested, rigorous biochemical study\",\n      \"pmids\": [\"27166796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ST3GAL1 and ST3GAL2 both function as cellular O-glycan sialyltransferases acting on Galβ1,3GalNAc residues in hematopoietic and megakaryocytic cells. CD34, CD43, and GPIbα are major glycoprotein substrates shared by ST3GAL1 and ST3GAL2, while GPIIb O-sialylation relies predominantly on ST3GAL2. Loss of both ST3GAL1 and ST3GAL2 dramatically impairs megakaryocyte proplatelet formation.\",\n      \"method\": \"ST3GAL1/ST3GAL2 single and double knockout human iPSC lines, differentiation to HPCs and MKs, peanut agglutinin lectin binding assay, substrate glycoprotein identification, proplatelet formation assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype, substrate identification by lectin binding in defined KO backgrounds, multiple orthogonal assays in one study\",\n      \"pmids\": [\"35507766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ST3GAL1 overexpression in ovarian cancer cells increases cell growth, migration, invasion, and paclitaxel resistance in vitro and in vivo. TGF-β1 increases ST3GAL1 expression and induces EMT; ST3GAL1 knockdown inhibits TGF-β1-induced EMT marker expression.\",\n      \"method\": \"ST3GAL1 overexpression/knockdown in ovarian cancer cell lines, paclitaxel resistance assays in vitro and in mouse xenograft, TGF-β1 stimulation with EMT marker western blotting\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss- and gain-of-function with in vivo validation, TGF-β1 pathway linkage, but molecular substrate of sialylation not identified\",\n      \"pmids\": [\"30375371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ST3GAL1 synthesizes sialoglycans capable of engaging the Siglec-7 and Siglec-9 immunoreceptors on immune cells, enabling prostate cancer immune evasion. ST3GAL1 levels inversely correlate with androgen signaling in prostate tumors.\",\n      \"method\": \"ST3GAL1 expression analysis in prostate tumor specimens, Siglec-7/9 ligand detection, functional immune evasion assays, modulation by enzalutamide\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Siglec-7/9 ligand identification linked to ST3GAL1 activity with functional immune readouts; single lab\",\n      \"pmids\": [\"38448753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST3GAL1 sialylates neuropilin-1 (NRP1), and this sialylation increases NRP1 binding affinity toward EGFR at the molecular level. ST3GAL1 silencing impairs cell migration and wound healing linked to reduced CAPN2 activity as a consequence of diminished EGF/EGFR signaling. ST3GAL1 silencing also augments sensitivity to cetuximab-mediated cell lysis.\",\n      \"method\": \"Identification of NRP1 as ST3GAL1 substrate, co-IP/binding affinity assays between NRP1 and EGFR, ST3GAL1 siRNA knockdown, migration/wound healing assays, CAPN2 activity assay, cetuximab cytotoxicity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification with molecular binding affinity measurement and functional downstream signaling readouts, single lab\",\n      \"pmids\": [\"40024474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RANKL activates c-FOS to drive ST3GAL1 transcription in osteoclasts, promoting osteoclastogenesis. Estrogen-bound ERα competes with TRAF6 and suppresses this c-FOS-dependent ST3GAL1 induction. In vivo sialidase treatment in estrogen-deficient models reduces osteoclast-mediated bone loss, mimicking estradiol effects.\",\n      \"method\": \"Transcriptional pathway analysis (c-FOS/ST3GAL1), ERα-TRAF6 competition assay, single-cell RNA sequencing of human bone, in vivo sialidase treatment in estrogen-deficient mouse models, serum sialic acid measurement in clinical cohort\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic transcriptional pathway established (RANKL→c-FOS→ST3GAL1) with ERα suppression mechanism and in vivo sialidase rescue, single study\",\n      \"pmids\": [\"41680135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NRF2 directly binds to two key regions on the ST3GAL1 promoter (−1107~−771 and −437~+195) to enhance ST3GAL1 transcription in colorectal cancer. ST3GAL1 mediates sialylation of integrin-α6β4 at specific O-glycosylation sites (ITGA6: S934, S937, T944; ITGB4: S1515, S1517, T1524), thereby activating downstream FAK/SRC signaling and promoting metastasis. Catalytic-domain mutant ST3GAL1 (H299A) has no tumor-promoting effect, confirming dependence on sialyltransferase activity.\",\n      \"method\": \"Dual luciferase mutation assay and ChIP-qPCR for NRF2-ST3GAL1 promoter interaction, lectin affinity immunoprecipitation, site-directed mutagenesis of O-glycosylation sites on integrin-α6β4, catalytic dead mutant (H299A), FAK/SRC phosphorylation assays, in vivo xenograft models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — catalytic mutagenesis (H299A) confirms enzyme activity requirement, site-directed mutagenesis identifies specific substrate O-glycosylation sites, ChIP-qPCR and luciferase validate transcriptional regulation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"41904587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST3GAL1 directly binds MUCL1 and catalyzes its sialylation, increasing MUCL1 protein stability and promoting breast cancer cell proliferation, migration, invasion, and in vivo tumor growth and lung metastasis. These effects are reversed by sialyltransferase inhibitor Lith-O-Asp or MUCL1 knockdown.\",\n      \"method\": \"Co-IP demonstrating ST3GAL1-MUCL1 direct binding, sialylation assay, ST3GAL1 knockdown/overexpression, MUCL1 stability assay, Lith-O-Asp inhibitor treatment, in vivo tumor and metastasis models\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification by Co-IP, functional rescue with inhibitor and MUCL1 KD, in vivo validation; single lab\",\n      \"pmids\": [\"41770470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST3GAL1 directly glycosylates VEGF-A (confirmed by Duolink proximity ligation assay and co-immunoprecipitation) and activates FAK/paxillin signaling, promoting VEGF-A expression and EMT in endometrial cancer. ST3GAL1 inhibition with soyasaponin I (SsaI) reduces VEGF-A signaling and synergizes with bevacizumab in vivo.\",\n      \"method\": \"Duolink proximity ligation assay, co-immunoprecipitation, ST3GAL1 knockdown, SsaI pharmacological inhibition, in vitro migration/invasion assays, in vivo xenograft with bevacizumab combination\",\n      \"journal\": \"International journal of gynaecology and obstetrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate interaction confirmed by two proximity methods (PLA + co-IP), FAK/paxillin pathway readout, in vivo validation; single lab\",\n      \"pmids\": [\"40497576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ST3GAL1 knockdown significantly reduces Siglec-7 ligand expression on liver cancer cells (HCC), enhancing susceptibility to NK cell-mediated cytotoxicity and cetuximab-induced ADCC. Sorafenib-resistant HCC cells display hypersialylation with increased Siglec-7/9 ligands, conferring NK cell evasion that is reversed by ST3GAL1 silencing.\",\n      \"method\": \"ST3GAL1 siRNA knockdown, Siglec-7/9 ligand surface staining, NK cell cytotoxicity assays, ADCC assay, sorafenib-resistant cell lines\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional immune cytotoxicity assays with defined ST3GAL1 loss-of-function, ligand profiling; single lab\",\n      \"pmids\": [\"41961075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A universal glycosyltransferase continuous (UGC) assay revealed that ST3GAL1 inhibition by soyasaponin-1 is time-dependent, and ST3GAL1 is the most responsive of three tested glycosyltransferases (IC50 ~37 µM vs. 52 µM for FUT1 and 886 µM for C1GALT1). The kinetic parameters (Km) of ST3GAL1 were standardized using CMP as nucleotide donor.\",\n      \"method\": \"Continuous fluorometric glycosyltransferase assay (UGC), kinetic parameter determination, dose-response inhibition with soyasaponin-1\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro enzymatic kinetics assay with defined inhibitor, but single lab and primarily a methods development study; IC50 values provided\",\n      \"pmids\": [\"38645360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Androgen-androgen receptor (AR) signaling in the submandibular gland negatively regulates ST3GAL1 (and ST3GAL4), reducing MUC10 sialylation. This correlates with sex differences in oral microbiota composition, as female-preferring bacteria such as Akkermansia muciniphila can assimilate mucin by degrading terminal sialic acids.\",\n      \"method\": \"Neuraminidase treatment showing sialic acid contribution to MUC10 mobility on SDS-PAGE, androgen manipulation experiments, RT-PCR for ST3GAL1 expression, microbiota profiling\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — AR signaling linkage to ST3GAL1 expression shown, MUC10 sialylation role inferred from neuraminidase experiment; functional consequence in microbiota is correlative; single lab, limited mechanistic detail\",\n      \"pmids\": [\"39572079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AR and MYC cooperatively repress ST3GAL1 transcription in prostate cancer cells, limiting synthesis of Siglec-7 ligands. Supraphysiological androgen levels produce distinct glycopeptide profiles compared with physiological androgen levels, with O-glycans as major substrates for sialylation in prostate cancer.\",\n      \"method\": \"AR and MYC manipulation in prostate cancer cells, glycopeptide profiling, Siglec-7 ligand quantification, transcriptional regulation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — preprint, single lab, mechanistic detail in abstract is limited; cooperative AR/MYC repression of ST3GAL1 shown but not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ST3GAL1 overexpression in bladder cancer cells (converting T antigen to sialyl-T antigen) increases sensitivity to oxidative damage and modulates the transcriptome toward genomic instability. BCG challenge of ST3GAL1-overexpressing cells induces stronger macrophage secretion of IL-6, IL-1β, TNFα, and IL-10 compared to T-antigen-expressing cells.\",\n      \"method\": \"Retroviral transduction of ST3GAL1 cDNA into bladder cancer cells, whole-genome microarray, multiplex cytokine immunoassay of macrophage secretome, BCG challenge assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ST3GAL1 expression manipulation with defined T→sialyl-T conversion, transcriptomic and cytokine functional readouts; multiple methods in single study\",\n      \"pmids\": [\"29454317\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ST3GAL1 is a type II transmembrane sialyltransferase that catalyzes the transfer of sialic acid in α2,3-linkage to Galβ1,3GalNAc (core 1 O-glycan) residues on diverse glycoprotein substrates including CD55, CD18/LFA-1, vasorin, GFRA1, NRP1, AXL, GPIbα, CD34, CD43, integrin-α6β4, VEGF-A, and MUCL1; this substrate sialylation modulates receptor dimerization and signaling (AXL, EGFR/NRP1, VEGF-R2, FAK/SRC, PI3K-AKT), complement evasion (CD55), immune checkpoint engagement (Siglec-7/9 via sialoglycans), and T cell trafficking (LFA-1 endocytic recycling via CD18), while its transcription is regulated by TGF-β1, GDNF, SOX2-GLI1, NRF2, c-FOS/RANKL, and androgen-AR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ST3GAL1 is a sialyltransferase that transfers sialic acid in α2,3-linkage onto the Galβ1,3GalNAc (core 1 / T-antigen) disaccharide of O-glycans, an activity reconstituted with recombinant enzyme on defined galactoside substrates and dependent on an intact catalytic domain (H299A mutant is inactive and non-tumorigenic) [#6, #12]. Through this O-glycan sialylation it remodels the glycocalyx of numerous cell-surface and secreted proteins to tune receptor signaling, complement and immune evasion, and cell migration. It sialylates receptor tyrosine kinase pathway components to promote oncogenic signaling: AXL (driving dimerization and melanoma invasion) [#0], GFRA1 (enabling GDNF-induced RET/AKT/ERα phosphorylation) [#4], neuropilin-1 (increasing NRP1–EGFR binding affinity and EGF/EGFR-driven migration) [#10], and integrin-α6β4 at defined O-glycosylation sites to activate FAK/SRC and metastasis [#12]; it also sialylates VEGF-A to drive FAK/paxillin signaling and EMT [#14] and stabilizes MUCL1 to promote proliferation and metastasis [#13]. ST3GAL1-dependent sialoglycans engage the inhibitory immunoreceptors Siglec-7 and Siglec-9 to evade NK- and complement-mediated killing across prostate, liver, and breast cancers, including sialylation of CD55 that reduces C3 deposition [#2, #9, #15]. In immune and hematopoietic cells it sialylates CD18 to alter LFA-1 endocytic recycling and T-cell trafficking [#3] and, redundantly with ST3GAL2, sialylates CD34, CD43, and GPIbα to support megakaryocyte proplatelet formation [#7]. ST3GAL1 transcription is controlled by multiple inducers and repressors including SOX2-GLI1, TGF-β1, GDNF, NRF2, and RANKL/c-FOS, with androgen-AR and estrogen-ERα signaling acting as negative regulators [#0, #1, #11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that human ST3GAL1 is itself a catalytically active enzyme on the core 1 disaccharide grounded all later substrate-specific claims in a defined biochemical activity.\",\n      \"evidence\": \"Recombinant human ST3GAL1 expressed in E. coli, in vitro sialylation assays on lactose, LacNAc, and Galβ1,3GalNAc substrates\",\n      \"pmids\": [\"27166796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the catalytic or transmembrane domain\", \"Donor/acceptor kinetics on native glycoprotein substrates not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked ST3GAL1 to receptor-mediated growth signaling and to cytokine/oxidative phenotypes, moving it from an enzyme to a driver of cancer cell behavior.\",\n      \"evidence\": \"siRNA knockdown with GFRA1 substrate identification and RET/AKT/ERα phosphorylation readouts in breast cancer; retroviral overexpression in bladder cancer with transcriptomic and macrophage cytokine profiling\",\n      \"pmids\": [\"30040982\", \"29454317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GFRA1 O-glycan structures not characterized by MS\", \"Mechanism linking sialyl-T conversion to oxidative sensitivity unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ST3GAL1 sialylation can dampen rather than promote signaling, and identified a TGF-β1 feedback loop, refining the model of how it tunes pathways.\",\n      \"evidence\": \"LC-MS/MS O-glycan profiling of secreted vasorin, neuraminidase desialylation, Smad2/3 phosphorylation and HUVEC tube formation assays, MCF7 xenograft\",\n      \"pmids\": [\"30252131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same VASN sialoforms operate in vivo across tumor types not tested\", \"Stoichiometry of VASN sialylation versus TGF-β1 binding not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined ST3GAL1 as an oncogenic transcriptional target and a node controlling immune evasion and receptor activation through distinct substrates.\",\n      \"evidence\": \"SOX2-GLI1-induced ST3GAL1 with AXL substrate identification and metastasis assays (melanoma); CD55 O-glycan MS with C3 deposition/complement/ADCC assays (breast); MEG3→c-Jun→ST3GAL1 axis with EGFR sialylation and PI3K-AKT readouts (RCC)\",\n      \"pmids\": [\"33203881\", \"33177111\", \"32737220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct sialylation site mapping on AXL and EGFR not resolved\", \"Context-dependent opposite effects on EGFR versus other RTKs unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic dissection in iPSC-derived cells showed ST3GAL1 acts redundantly with ST3GAL2 on shared core 1 substrates required for blood cell function.\",\n      \"evidence\": \"ST3GAL1/ST3GAL2 single and double knockout iPSC lines, PNA lectin binding, substrate identification, proplatelet formation assays\",\n      \"pmids\": [\"35507766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each enzyme per substrate not fully partitioned\", \"Physiological platelet phenotype in vivo not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified CD18 as a substrate whose sialylation misroutes T-cell trafficking, establishing ST3GAL1 as a barrier to adoptive cell therapy with a defined rescue.\",\n      \"evidence\": \"In vivo CRISPR-Cas9 loss-of-function screen, CD18 substrate identification, LFA-1 endocytic recycling assays, βII-spectrin overexpression rescue in CAR T cells\",\n      \"pmids\": [\"37069398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CD18 sialylation and recycling machinery incompletely defined\", \"Generalizability across T-cell subsets not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ST3GAL1 to Siglec-7/9 ligand synthesis as a mechanism of cancer immune evasion and provided standardized inhibitor kinetics.\",\n      \"evidence\": \"Siglec-7/9 ligand detection and immune evasion assays in prostate cancer with enzalutamide modulation; UGC fluorometric kinetic assay with soyasaponin-1 IC50 determination\",\n      \"pmids\": [\"38448753\", \"38645360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific glycoprotein carriers of Siglec ligands not identified\", \"Inhibitor selectivity in cells beyond in vitro kinetics untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the substrate repertoire (NRP1, VEGF-A, MUCL1) and reinforced the Siglec-mediated immune evasion model while implicating ST3GAL1 in therapy resistance.\",\n      \"evidence\": \"Co-IP/PLA substrate confirmation and binding affinity assays for NRP1-EGFR, VEGF-A FAK/paxillin signaling with bevacizumab synergy, MUCL1 stability with Lith-O-Asp inhibitor; Siglec-7 ligand and NK/ADCC assays in sorafenib-resistant HCC\",\n      \"pmids\": [\"40024474\", \"40497576\", \"41770470\", \"41961075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sialylation sites on NRP1 and VEGF-A not mapped\", \"Whether MUCL1 stabilization is direct consequence of sialylation untested in cell-free system\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved transcriptional control nodes and proved catalytic dependence, mapping specific substrate O-glycosylation sites and linking ST3GAL1 to bone homeostasis.\",\n      \"evidence\": \"NRF2 ChIP-qPCR/luciferase promoter mapping, integrin-α6β4 site-directed mutagenesis with H299A catalytic-dead mutant and FAK/SRC readouts (CRC); RANKL→c-FOS induction, ERα-TRAF6 competition, and in vivo sialidase rescue in bone\",\n      \"pmids\": [\"41904587\", \"41680135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether bone osteoclast substrate(s) of ST3GAL1 are defined\", \"Integration of the many transcriptional regulators in a single cell context unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which structural features dictate ST3GAL1 substrate selection across its diverse glycoprotein targets and how opposing signaling outcomes (e.g., AXL/RTK activation versus EGFR inhibition) are determined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for acceptor specificity\", \"Context-dependent pro- versus anti-signaling effects unexplained\", \"Sialylation site maps absent for most substrates\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 7, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 12, 13]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 9, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AXL\", \"VASN\", \"CD55\", \"CD18\", \"GFRA1\", \"NRP1\", \"MUCL1\", \"VEGFA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}