The prostate cancer study by Tsai and colleagues (Cancer Research, 2016) established that galectin-4, a tandem-repeat beta-galactoside-binding lectin upregulated in metastatic prostate cancer, binds autonomously to core 1 O-glycans synthesized by C1GALT1 on cancer cells, clusters and activates multiple receptor tyrosine kinases (RTKs) such as EGFR and HER2, and drives epithelial–mesenchymal transition, invasion, and metastasis. Four linked questions arising from these findings remain open: whether intracellular galectin-4 or mucin proteins such as MUC1 contribute to RTK interaction or signal amplification; by what molecular mechanism C1GALT1 depletion selectively reduces EGFR and IGF1R protein abundance (translation versus proteolysis versus altered trafficking); what regulatory inputs — tumor microenvironmental stress, castration, therapy — drive galectin-4 upregulation in metastatic prostate cancer; and whether the galectin-4–core 1 O-glycan axis is therapeutically targetable in preclinical models.

Background

Galectins are a family of soluble beta-galactoside-binding proteins that lack a classical secretion signal and act both extracellularly, by cross-linking glycosylated cell-surface receptors into a signaling-competent lattice, and intracellularly, by modulating signaling and trafficking. Galectin-4 is a tandem-repeat galectin with two carbohydrate-recognition domains, normally abundant in intestinal epithelium. Mucin-type O-glycosylation is the attachment of N-acetylgalactosamine (GalNAc) to serine/threonine residues of membrane and secreted proteins; the core 1 structure (also called the T antigen, Gal-beta1-3GalNAc) is synthesized by C1GALT1 (T-synthase, the core 1 beta1,3-galactosyltransferase) and serves as the scaffold for most complex O-glycans. Receptor tyrosine kinases (RTKs) — such as EGFR (the epidermal growth factor receptor), other HER2/ErbB family members, and IGF1R (the insulin-like growth factor 1 receptor) — are growth-factor receptors whose dimerization and autophosphorylation control proliferation, survival, and epithelial–mesenchymal transition (EMT, a program of adhesion loss and invasiveness). Metastatic castration-resistant prostate cancer (CRPC) is the lethal stage of the disease, resistant to androgen-deprivation therapy, and notably resistant to HER2-targeted agents despite HER2 signaling contributing to androgen-receptor activity — an enigma that motivates understanding alternative layers of RTK regulation. Tsai et al. (Cancer Research 2016) reported that prostate cancer xenografts giving spontaneous metastases expressed high galectin-4 together with EGFR/HER2-signaling and O-glycosylation gene signatures; galectin-4 correlated with poor patient survival; recombinant galectin-4 bound several RTKs and stimulated their autophosphorylation, activating ERK/AKT, fibronectin, and Twist1 while repressing E-cadherin; and these effects depended on C1GALT1-mediated core 1 O-glycosylation, with C1GALT1 depletion selectively lowering EGFR and IGF1R protein abundance. The same group subsequently showed (FASEB Journal 2018) that galectin-4, C1GALT1, and the sialyltransferase ST3GAL1 rise coordinately during CRPC progression, that MYC drives C1GALT1/ST3GAL1 expression to create a feed-forward galectin-glycan circuit engaging RTK signaling and SOX9-dependent cancer stemness, and that combined high C1GALT1 and galectin-4 expression predicts poor overall survival. Field reviews through 2026 (including a dedicated prostate cancer glycobiology update) still describe the galectin-4–C1GALT1 axis as linked to castration resistance and poor prognosis without resolving its mechanistic branches, and no galectin-4- or core-1-directed agent has demonstrated efficacy in prostate cancer models, even as the first systematic galectin-4 inhibitor libraries and selective galectin-4C inhibitors have now been synthesized.

Problem Statement

For the galectin-4–core 1 O-glycan signaling axis that drives metastatic progression of prostate cancer (Tsai et al., Cancer Research 2016), determine: (1) whether intracellular galectin-4, or mucin proteins such as MUC1 (a cell-surface mucin carrying core 1 O-glycans) that might serve as glycan carriers, contribute to galectin-4-mediated receptor tyrosine kinase (RTK) interaction or signal amplification, as opposed to a purely extracellular lectin-lattice mechanism; (2) the molecular mechanism by which depleting C1GALT1 (core 1 beta1,3-galactosyltransferase, T-synthase) selectively reduces EGFR (epidermal growth factor receptor) and IGF1R (insulin-like growth factor 1 receptor) protein abundance in prostate cancer cells — possible mechanisms include reduced translation, increased proteolysis, and altered trafficking/degradation of these receptors; (3) the regulatory inputs that upregulate galectin-4 expression from the LGALS4 gene (the gene encoding galectin-4) in metastatic prostate cancer, including candidate tumor-microenvironmental stresses (e.g., IL-30/inflammatory crosstalk), castration, and other therapies, and the transcriptional mechanism involved; and (4) whether the axis is therapeutically targetable in preclinical models of metastatic/castration-resistant prostate cancer — which candidate interventions would be tested, and how the efficacy and safety of those interventions would be assessed in such models. These four questions jointly constitute the open objective: a mechanistic and translational account of how galectin-4 binding to C1GALT1-dependent O-glycans sustains RTK signaling and metastasis, and whether that axis can be drugged in advanced prostate cancer. For (1), either a positive or a negative determination resolves the sub-question provided the evidence distinguishes an intracellular or mucin-carrier contribution from a purely extracellular lectin-lattice mechanism; for (2), discriminating at least one of the three candidate mechanisms resolves the sub-question.

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