Glycosylation modification is a common post-translational modification process in cells, involving the covalent attachment of one or more sugar groups to proteins or other organic molecules. This modification affects protein folding, stability, activity, and intercellular signaling. There are two main types of glycosylation modification: N-glycosylation and O-glycosylation. For example, many cell surface proteins, cytokines or hormone receptors, regulate their functions through glycosylation modification.
Abnormal glycosylation patterns are often associated with a variety of diseases, such as cancer, autoimmune diseases, and neurodegenerative diseases. In many types of cancer, the sugar chain structure of Glycoproteins on the surface of tumor cells changes, and these changes can serve as biomarkers of disease. For example, CA125 is a well-known glycoprotein marker in ovarian cancer, and its glycosylation status is closely related to the disease stage and prognosis.
Since glycosylation directly affects protein function and cell-to-cell interactions, glycosylation pathways and related enzymes have become potential drug targets. The glycosylation pattern of Antibody Drugs, especially in the treatment of certain types of cancer, has an important impact on their therapeutic effects. Regulating the glycosylation status of these drugs can enhance their efficacy or reduce side effects.
Glycosylation modification may affect cell growth, migration, and immune escape mechanisms, which is particularly important for cancer invasiveness and metastasis. Studying these mechanisms can help us better understand the development of the disease and potential treatment strategies.
Due to the universality of glycosylation modification and its key role in disease, this field has become a hot spot for scientific research, attracting extensive scientific research interest and investment. By deeply studying the biological process of glycosylation and its role in disease, new diagnostic methods and therapeutic strategies can be promoted.
Studies have found that abnormal glycosylation of prosaposin (pSAP) in tumor-associated dendritic cells plays an important regulatory role in immune response. This protein and its monosaponin homologues promote the effective presentation of tumor Antigens by regulating the disintegration of tumor cell-derived apoptotic bodies. In the tumor microenvironment, transforming growth factor-β (TGF-β) induces hyperglycosylation of pSAP and its subsequent secretion, ultimately leading to the depletion of lysosomal saponins.
Analysis of clinical samples showed that dendritic cells of melanoma patients had hyperglycosylation of pSAP, and reconstruction with pSAP rescued the activation of tumor-infiltrating T cells. Targeting dendritic cells with recombinant pSAP can trigger tumor protection and enhance immune checkpoint therapy. This finding provides a new intervention strategy for combined immune checkpoint therapy.
Gastric cancer is often accompanied by the loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear.
Muc6 knockout mice spontaneously develop pangastritis and invasive gastric cancer. Muc6-deficient tumor growth is dependent on the activation of mitogen-activated protein kinases mediated by upregulation of Golgi phosphoprotein 3 induced by Golgi stress. Glycomic Analysis revealed abnormal expression of mannose-rich N-glycans in gastric tumors, which correlated with the loss of MUC6 expression as detected by banana lectin. The researchers also identified the precursor of clusterin as a binding partner for mannose glycans. The research team further found activation of mitogen-activated protein kinases, Golgi stress response, and abnormal mannose expression in Cosmc and A4gnt-deficient models. Banana lectin-drug conjugates were shown to be effective therapeutics for mannose-rich gastric cancer in mice and humans, providing new ideas for precision therapy targeting glycan abnormalities.
Historically, melanoma morbidity and mortality have been higher in males than in females. Although emerging studies highlight the tumorigenic role of the male hormone androgen and its receptor (AR) in melanoma, the cellular and molecular mechanisms underlying these sex-related differences are unclear. This study describes a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). The study further reveals that AR-induced FUT4 fucosylation of L1 cell adhesion molecule (L1CAM) is required for FUT4 to increase metastatic capacity.
Tumor microarray and gene expression analysis demonstrated that AR-FUT4-L1CAM-AJs signaling correlates with pathological stage in melanoma patients. By describing a critical androgen-triggered signaling pathway that enhances metastatic invasiveness, these findings help explain sex-related differences in clinical outcomes and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.
Dysregulated glucose metabolism is a fundamental feature of cancer. This is often manifested as an increased rate of glycolysis with a concomitant decrease in the rate of tricarboxylic acid (TCA) cycle metabolism compared with normal cells. Mechanistic studies have shown that O-GlcNAc regulates the TCA cycle in colorectal cancer cells. Depletion of OGT, the sole transferase of O-GlcNAc, significantly increased TCA cycle metabolism in colorectal cancer cells. OGT-catalyzed O-GlcNAc modification of c-Myc at site serine 415 (S415) increased c-Myc stability, thereby transcriptionally upregulating the expression of pyruvate dehydrogenase kinase 2 (PDK2). PDK2 phosphorylates pyruvate dehydrogenase (PDH) to inhibit the activity of the mitochondrial pyruvate dehydrogenase complex, thereby reducing mitochondrial pyruvate metabolism, suppressing the production of reactive oxygen species, and promoting xenograft tumor growth. In addition, c-Myc S415 glycosylation levels were positively correlated with PDK2 expression levels in clinical colorectal tumor tissues. This study reveals that the OGT-c-Myc-PDK2 axis is a key mechanism linking oncoprotein activation to dysregulated glucose Metabolism in colorectal cancer.
Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to control symptoms, but there is currently no curative treatment. Altered glycosylation of tumor cells is a hallmark of Cancer and an important driver of the malignant phenotype. In prostate cancer, the sialyltransferase ST6 GAL1 is upregulated, and ST6 GAL1-mediated abnormal sialylation of N-glycans can promote prostate tumor growth and disease progression.
This study found that ST6 GAL1 is upregulated in prostate cancer patients whose tumors have spread to the bone and can promote prostate cancer bone metastasis in vivo. It is also involved in modifying the pre-metastatic niche to bone resorption to promote a vicious cycle, promoting the development of M2-like macrophages, and regulating immunosuppressive sialoglycans. In addition, inhibition of Sialylation can block the spread of prostate tumors to the bone.
This study identified the important role of ST6 GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provided proof-of-concept data showing that inhibition of sialylation can inhibit the spread of prostate tumors to the bone, and highlighted sialic acid blockade as a new strategy for developing new treatments for patients with advanced prostate cancer.
Fig. 1 c-Myc O-GlcNAcylation regulates the TCA cycle and tumor growth in CRC. (Hodgson, et al., 2024)
In summary, glycosylation research plays a key role in the biomedical field, especially in the occurrence and progression of cancer. By studying how glycosylation modifications affect protein function and cell signaling, researchers can reveal the molecular mechanisms of disease, develop new biomarkers, and explore potential therapeutic targets. For example, analyzing the role of specific glycosylation enzymes in tumors can help understand their role in tumor growth and metastasis, thereby providing new strategies and methods for cancer treatment.
Reference
