Affinage

B3GNT3

N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 3 · UniProt Q9Y2A9

Length
372 aa
Mass
42.5 kDa
Annotated
2026-06-09
13 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

B3GNT3 is a β-1,3-N-acetylglucosaminyltransferase that functions in cancer cells through both glycosyltransferase-dependent and catalysis-independent mechanisms to promote survival, invasion, and stemness (PMID:37479744, PMID:41838238). In its enzymatic role, B3GNT3 N-glycosylates 4F2hc (SLC3A2), stabilizing the protein and enhancing its interaction with xCT to sustain system Xc- activity and intracellular glutathione, such that its loss sensitizes pancreatic cancer cells to ferroptosis (PMID:37479744). Independent of catalysis, B3GNT3 physically interacts with NFKB2 to drive p100 phosphorylation, processing to p52, and nuclear accumulation, thereby activating non-canonical NF-κB signaling to promote proliferation, invasion, anoikis resistance, and EMT — a function fully retained by a catalytically inactive mutant (PMID:41838238). B3GNT3 expression is transcriptionally driven by ETV4, which binds its promoter and engages downstream TGF-β signaling to support proliferation, migration, and EMT in liver cancer (PMID:37523127). Through control of cell-surface O-glycosylation, B3GNT3 also modulates malignant phenotypes and downstream FAK/Src/Akt/ERK signaling (PMID:24118321).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2013 Medium

    Established the first functional link between B3GNT3 and malignant behavior by showing its O-glycan modifying activity restrains tumor cell migration and invasion through adhesion/survival signaling.

    Evidence B3GNT3 overexpression and knockdown in neuroblastoma cells with migration/invasion assays and phosphoprotein western blotting

    PMID:24118321

    Open questions at the time
    • No direct glycan substrate mapping for the signaling changes
    • Direction of effect (tumor-suppressive) contrasts with later oncogenic findings in other cancers
    • Single cell-line context
  2. 2018 Medium

    Implicated B3GNT3 in cancer stem cell maintenance, linking its glycosyltransferase function to surface markers and self-renewal programs.

    Evidence Knockdown and CRISPR KO of glycosyltransferases in pancreatic cancer stem cells with tumorsphere, clonogenicity, and marker assays

    PMID:30466404

    Open questions at the time
    • B3GNT3-specific CRISPR KO not performed (co-studied with GALNT3)
    • Direct glycosylation of CD44v6/ESA not demonstrated
    • Mechanistic link to SOX2/OCT3/4 indirect
  3. 2021 Low

    Connected B3GNT3 to small GTPase activation, proposing a route to invasion via RhoA/RAC1.

    Evidence Loss- and gain-of-function in endometrial cancer cells with GTP-RhoA/RAC1 western blots and migration assays

    PMID:33683574

    Open questions at the time
    • No biochemical link between glycosyltransferase activity and GTPase activation
    • Single method type (active-GTPase western blot)
    • Single lab
  4. 2023 High

    Defined a discrete enzymatic mechanism by which B3GNT3 controls ferroptosis resistance through N-glycosylation and stabilization of the system Xc- subunit 4F2hc.

    Evidence Glycoproteomics, B3GNT3 KO, catalytic and glycosylation-site mutant rescue, Co-IP, and orthotopic in vivo models in PDAC

    PMID:37479744

    Open questions at the time
    • Whether other glycoprotein substrates contribute to ferroptosis control
    • In vivo relevance to therapy beyond models studied
  5. 2023 Medium

    Placed B3GNT3 within a transcriptional circuit, showing it is a direct ETV4 target that relays into TGF-β signaling to drive EMT.

    Evidence ChIP, dual-luciferase reporter, knockdown epistasis, and TGF-β inhibitor treatment in liver cancer cells

    PMID:37523127

    Open questions at the time
    • Mechanism by which B3GNT3 activates TGF-β signaling not defined
    • Enzymatic vs non-enzymatic contribution not separated
    • Single lab
  6. 2025 Medium

    Identified a physical partner (FUT3) whose interaction with B3GNT3 activates NF-κB to promote autophagy-driven chemoresistance.

    Evidence Co-IP, RNA-seq, and FUT3 knockdown xenograft in PDAC

    PMID:41366466

    Open questions at the time
    • Enzymatic contribution of B3GNT3 to the complex not tested
    • Reciprocal validation and structural basis of interaction absent
    • Single lab
  7. 2026 High

    Revealed a catalysis-independent oncogenic mechanism: B3GNT3 binds NFKB2 to drive non-canonical NF-κB activation, decoupling its tumor-promoting function from glycosyltransferase activity.

    Evidence IP-MS, Co-IP, catalytic-inactive mutant, NFKB2 genetic ablation rescue, and xenograft in lung adenocarcinoma

    PMID:41838238

    Open questions at the time
    • Structural basis of B3GNT3-NFKB2 interaction unknown
    • How a glycosyltransferase accesses cytoplasmic/nuclear NF-κB machinery unresolved
    • Relationship to canonical NF-κB/FUT3 axis not integrated
  8. 2026 Low

    Positioned B3GNT3 downstream of a TCN1/EGFR axis regulating proliferation, metastasis, and glycolysis in NSCLC.

    Evidence qRT-PCR, western blot, functional assays, KEGG analysis, rescue experiments, and xenograft

    PMID:41579832

    Open questions at the time
    • Direct biochemical demonstration of EGFR-mediated B3GNT3 regulation absent
    • Pathway placement inferred from rescue only
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how B3GNT3's dual enzymatic (glycan-modifying) and non-enzymatic (protein-interaction) functions are coordinated within a single cell and across tumor types.
  • No structural model of B3GNT3 protein-protein interactions
  • Subcellular routing reconciling Golgi glycosyltransferase activity with NF-κB engagement undefined
  • Context dependence of tumor-suppressive vs oncogenic roles unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 1
Partners
FUT3NFKB2SLC3A2

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 B3GNT3 catalyzes N-glycosylation of 4F2hc (SLC3A2), thereby stabilizing the 4F2hc protein and enhancing the interaction between 4F2hc and xCT (system Xc-); knockout of B3GNT3 or deletion of its enzymatically active form sensitizes PDAC cells to ferroptosis by impairing system Xc- activity and reducing intracellular glutathione. N- and O-linked glycoproteomics, B3GNT3 knockout, catalytic mutant rescue, reconstitution of 4F2hc-deficient cells with WT vs. glycosylation-mutated 4F2hc, co-immunoprecipitation, in vitro and orthotopic in vivo models Cell death and differentiation High 37479744
2013 B3GNT3 overexpression suppresses T antigen (core 1 O-glycan) formation in neuroblastoma cells and reduces malignant phenotypes (migration, invasion) by decreasing phosphorylation of FAK, Src, paxillin, Akt, and ERK1/2; conversely, B3GNT3 knockdown enhances these phenotypes. B3GNT3 overexpression and knockdown in SK-N-SH cells, migration/invasion assays, western blotting for signaling phosphoproteins, immunohistochemistry on tumor tissues Cancer science Medium 24118321
2018 GALNT3 and B3GNT3 are overexpressed in pancreatic cancer stem cells (PCSCs) and knockdown of either glycosyltransferase decreases cell-surface expression of CD44v6 and ESA as well as self-renewal markers SOX2 and OCT3/4; CRISPR/Cas9-mediated GALNT3 KO also decreased self-renewal, clonogenicity, and migration of PCSCs. RT-qPCR, immunoblotting, immunofluorescence, transient knockdown and CRISPR/Cas9 KO, tumorsphere formation, clonogenicity, migration assays, side-population analysis BMC cancer Medium 30466404
2021 B3GNT3 promotes endometrial cancer cell growth, invasion, and migration through upregulation of GTP-bound (active) RhoA and RAC1; B3GNT3 downregulation reduces active RhoA and RAC1, while overexpression has the opposite effect. Loss- and gain-of-function B3GNT3 assays in HEC-1-A and KLE cells, CCK-8, clone formation, Transwell assays, western blotting for GTP-RhoA and GTP-RAC1 Genes & genomics Low 33683574
2023 ETV4 binds to the B3GNT3 promoter and activates B3GNT3 transcription; B3GNT3 in turn activates the TGF-β signaling pathway downstream of ETV4, promoting liver cancer cell proliferation, migration, invasion, and EMT. Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, qRT-PCR, B3GNT3 knockdown, TGF-β pathway inhibitor (SB525334) treatment, in vitro functional assays Genes & genomics Medium 37523127
2025 FUT3 physically interacts with B3GNT3 (co-immunoprecipitation) and this interaction activates NF-κB signaling, driving autophagy and chemoresistance in pancreatic ductal adenocarcinoma. Co-immunoprecipitation, RNA sequencing, RT-qPCR, western blotting, immunofluorescence, electron microscopy, FUT3 knockdown xenograft model European journal of medical research Medium 41366466
2026 B3GNT3 physically interacts with NFKB2, facilitating p100 phosphorylation and processing into p52 and its nuclear accumulation, thereby activating non-canonical NF-κB signaling to promote lung adenocarcinoma proliferation, invasion, anoikis resistance, and tumor growth; a catalytically inactive B3GNT3 mutant retains full ability to interact with NFKB2 and promote p100 processing and EMT, demonstrating the oncogenic function is independent of glycosyltransferase activity. Co-immunoprecipitation coupled with mass spectrometry, Co-IP, catalytic inactive mutant generation, NFKB2 genetic ablation rescue, transcriptomic profiling, gain/loss-of-function experiments, xenograft tumor model Cellular oncology (Dordrecht, Netherlands) High 41838238
2026 TCN1 positively regulates B3GNT3 expression via activation of the EGFR pathway; B3GNT3 knockdown suppresses proliferation, metastasis, EMT, and glycolysis in NSCLC cells, and overexpression of B3GNT3 partially rescues the effects of TCN1 knockdown. qRT-PCR, western blotting, CCK-8, Transwell, EMT and glycolysis assays, KEGG pathway analysis, rescue experiments, in vivo xenograft model Pathology, research and practice Low 41579832

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells. BMC cancer 50 30466404
2023 Targeting N-glycosylation of 4F2hc mediated by glycosyltransferase B3GNT3 sensitizes ferroptosis of pancreatic ductal adenocarcinoma. Cell death and differentiation 45 37479744
2013 B3GNT3 expression suppresses cell migration and invasion and predicts favorable outcomes in neuroblastoma. Cancer science 42 24118321
2015 B3GNT3 Expression Is a Novel Marker Correlated with Pelvic Lymph Node Metastasis and Poor Clinical Outcome in Early-Stage Cervical Cancer. PloS one 38 26709519
2018 B3GNT3 overexpression is associated with unfavourable survival in non-small cell lung cancer. Journal of clinical pathology 22 29483137
2020 B3GNT3 overexpression promotes tumor progression and inhibits infiltration of CD8+ T cells in pancreatic cancer. Aging 17 33316775
2021 B3GNT3 acts as a carcinogenic factor in endometrial cancer via facilitating cell growth, invasion and migration through regulating RhoA/RAC1 pathway-associated markers. Genes & genomics 12 33683574
2023 ETV4 facilitates proliferation, migration, and invasion of liver cancer by mediating TGF-β signal transduction through activation of B3GNT3. Genes & genomics 9 37523127
2023 The role of B3GNT3 as an oncogene in the growth, invasion and migration of esophageal cancer cells. Acta cirurgica brasileira 8 36995820
2023 Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma. Journal of thoracic disease 5 37065594
2026 TCN1 knockdown inhibits the progression and glycolysis of non-small cell lung cancer via regulating B3GNT3. Pathology, research and practice 0 41579832
2026 B3GNT3 facilitates NFKB2 processing and non-canonical NF-κB activation to drive lung adenocarcinoma progression. Cellular oncology (Dordrecht, Netherlands) 0 41838238
2025 FUT3-B3GNT3 interaction promotes pancreatic cancer progression and chemoresistance via NF-κB signaling mediated autophagy. European journal of medical research 0 41366466

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