Glycosylation Mechanisms in Cancer Biology

Glycosylation, the enzymatic attachment of carbohydrate moieties to proteins and lipids, profoundly influences tumour initiation, progression and metastasis. In cancer cells, alterations in glycan structure and abundance arise from dysregulated expression of glycosyltransferases and glycosidases, leading to changes in cell adhesion, signal transduction and immune recognition. Aberrant branching of N-linked glycans, increased sialylation and truncation of O-glycan chains on mucins collectively facilitate detachment from the primary tumour, invasion through the extracellular matrix and evasion of host immunity. Furthermore, dynamic O-GlcNAcylation of nuclear and cytosolic proteins modulates key oncogenic pathways by competing with phosphorylation on serine and threonine residues. Advances in mass-spectrometry-based glycoproteomics have begun to map site-specific glycosylation patterns across the cancer proteome, revealing glycan signatures that correlate with tumour subtype, stage and response to therapy. These insights underpin the development of glycan-targeted biomarkers and therapeutics, including glycomimetic inhibitors of lectin–glycan interactions and monoclonal antibodies directed against tumour-associated carbohydrate antigens.

Research from Nature Portfolio

A foundational workflow has been established for large-scale, high-accuracy identification of intact N-glycopeptides. By combining stepped-energy fragmentation with a dedicated search engine and rigorous quality control at the peptide, glycan and glycopeptide levels, this approach achieves both sensitivity and specificity across complex biological samples. Quantitative analysis using isotopic labelling has validated hundreds of site-specific glycan structures across diverse tissues, providing a benchmark for comparative studies in cancer biology. This method now supports the systematic characterisation of tumour-associated glycoproteomes and the discovery of glycosylation alterations that drive malignancy.

Glycosylation Mechanisms in Cancer Biology publication trend

The graph below shows the total number of articles in glycosylation mechanisms in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Glycosylation: Enzymatic addition of carbohydrate chains to proteins or lipids, affecting stability, localisation and function.

N-glycosylation: Attachment of oligosaccharides to the nitrogen atom of an asparagine residue within a consensus sequence.

O-glycosylation: Attachment of sugar moieties to the oxygen atom of serine or threonine residues, including O-GlcNAcylation.

Glycosyltransferase: Enzyme that catalyses the transfer of sugar residues from activated donors to acceptor molecules.

Lectin: Protein that specifically recognises and binds carbohydrate structures, mediating cell–cell and cell–matrix interactions.

Sialylation: Incorporation of sialic acid residues at terminal positions of glycan chains, often modulating immune recognition and cell adhesion.

Glycoproteomics: Mass-spectrometry-based analysis of glycopeptides to determine site-specific glycan structures and their relative abundances.

References

1. Glycosylation: mechanisms, biological functions and clinical implications. Signal Transduction and Targeted Therapy (2024).
2. Glycomimetics for the inhibition and modulation of lectins. Chemical Society Reviews (2023).
3. Hallmarks of glycosylation in cancer. Oncotarget (2016).
4. pGlyco 2.0 enables precision N-glycoproteomics with comprehensive quality control and one-step mass spectrometry for intact glycopeptide identification. Nature Communications (2017).
5. Altered Tumor-Cell Glycosylation Promotes Metastasis. Frontiers in Oncology (2014).
6. Dynamic Glycosylation of Nuclear and Cytosolic Proteins CLONING AND CHARACTERIZATION OF A UNIQUE O-GlcNAc TRANSFERASE WITH MULTIPLE TETRATRICOPEPTIDE REPEATS*. Journal of Biological Chemistry (1997).