B3GNT3 in cancer: catalysis-dependent and catalysis-independent mechanisms, biomarker readiness and therapeutic targeting.

Abstract

Aberrant glycosylation is a hallmark of malignant cells, yet individual glycosyltransferases are rarely evaluated as actionable targets. β-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) elongates poly-N-acetylglucosamine chains and is overexpressed in most solid tumors, where its abundance tracks with advanced stage and adverse outcomes. This critical review integrates structural, mechanistic, and clinical evidence to appraise B3GNT3 as a candidate biomarker and drug target. We organize its tumor-promoting activity into five functional modules and explicitly grade the evidence supporting each. A central theme is that B3GNT3 functions as a bifunctional signaling node through two separable routes: a catalytic arm (exemplified by 4F2hc N-glycosylation conferring ferroptosis resistance) and a catalysis-independent scaffolding arm (activating non-canonical NF-κB and epithelial-mesenchymal transition, retained by catalytically dead mutants). This duality reframes target selection: catalytic-site inhibitors address only one arm, whereas protein-protein interaction blockade or proteolysis-targeting chimeras potentially engage both. However, clinical translation is critically constrained by on-target toxicity and subcellular barriers inherent to a Golgi-resident enzyme. Only catalytic inhibition combined with ferroptosis inducers currently has in vivo support, and no selective B3GNT3 inhibitor exists. Furthermore, we establish B3GNT3 as a cancer-type-specific biomarker, noting a paradoxical inverse prognostic association in neuroblastoma. We conclude by proposing a phased roadmap from structural definition to early-phase clinical evaluation.

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