Under hyperglycemic conditions, there is aberrant activation of the Hedgehog pathway due to increased O-GlcNAcylation of the GLI1 and GLI2 transcription factors; this modification enhances their transcriptional activity. This study lays a foundation for inhibiting O-GlcNAcylation, particularly in cancer patients with diabetes or metabolic disease, in order to control metabolism, progression and/or drug resistance of breast cancer.
The editors of Laboratory Investigation present a collection of recent papers that explore the relationships between changes in the mammalian glycome and pathobiology. These studies describe new roles for glycans in heart disease, neurodegenerative diseases, genetic disorders, and several types of cancer.
Preferential expression of sialyl 6′-sulfo N-acetyllactosamine-capped O-glycans on high endothelial venules in human peripheral lymph nodes
The authors employed a monoclonal antibody, 297-11A, to determine preferential display of sialyl 6′-sulfo N-acetyllactosamine-capped O-glycans on high endothelial venules (HEVs) in human peripheral lymph nodes. These glycans were also displayed on HEV-like vessels in tumor-infiltrating lymphocyte aggregates in various cancers. Thus, 297-11A-positive sulfated glycans likely function in physiologic and pathologic lymphocyte trafficking.
Wisteria floribunda agglutinin staining for the quantitative assessment of cardiac fibrogenic activity in a mouse model of dilated cardiomyopathy
The authors propose that Wisteria floribunda agglutinin (WFA) staining on failing heart sections may be useful for quantitative assessment of cardiac fibrogenic activity. The fibrosis-specific WFA staining is mainly due to the WFA binding to fibrogenesis-related extracellular matrix N-glycoproteins. It is expected that cardiac WFA-binding glycoproteins may be circulating glyco-biomarkers for cardiac fibrogenesis.
Role of prion protein glycosylation in replication of human prions by protein misfolding cyclic amplification
Protein misfolding cyclic amplification (PMCA) is a technique able to detect minute amount of disease-related prion protein (PrPD), but limited results have been obtained with human prions with the exception of variant Creutzfeldt-Jakob disease (variant CJD). The study demonstrates that the use of substrates with deglycosylated PrP strongly increases PrPD amplification efficiency by PMCA for all tested CJD subtypes. The enhanced PMCA efficiency may allow for the developing of a sensitive, non-invasive, diagnostic tests for the different CJD subtypes based on body fluids or easily accessible peripheral tissues.
The authors have demonstrated an important new role of protein O-GlcNAcylation in regulating pancreatic cancer TRAIL resistance; and uncovered the contribution of O-GlcNAcylation to TRAIL activation-induced oligomerization of death receptor 5 and apoptosis signaling. These findings support the potential use of O-GlcNAcylation inhibitors to enhance efficacy of TRAIL therapy.
Gene δ-sarcoglycan was knocked out in pigs via gene editing and somatic cell cloning. Loss of expression led to α-, β-, and γ-sarcoglycan depletion in the cardiac and skeletal sarcolemma. Pigs exhibiting systolic dysfunction, myocardial tissue degeneration, and sudden death are promising for studying next-generation therapies for human genetic cardiomyopathy.
Glycodelin is a major endometrial glycoprotein. The authors analyzed glycan structures of endometrial carcinoma associated glycodelin and established a novel glycodelin-glycoform specific histochemical staining method. With this, they showed that glycodelin is differentially glycosylated in endometrial carcinoma tissue, as compared to normal endometrium, representing a neoantigen with potential clinical applications.
Characterization of colorectal mucus using infrared spectroscopy: a potential target for bowel cancer screening and diagnosis
Mucus was tested as a potential biological material for screening/early diagnosis of colorectal cancer using infrared spectroscopy. Based on a digital histopathology and statistical modeling approach, cancerous and non-cancerous samples were classified with an area under the curve performance of 95% based on mucus spectral profiles, indicating changes in the glycan component of mucins.
Molecular signatures of tumor progression in myxoid liposarcoma identified by N-glycan mass spectrometry imaging
This study on myxoid liposarcoma, based on mass spectrometry imaging of N-glycans, has revealed that increases in high-mannose-type as well as tri- and tetra-antennary complex-type N-glycans are associated with morphological progression of the disease. The increased abundance of tri-antennary complex-type glycans was also associated with a poor disease-specific survival for the patients.
This study demonstrates that NFAT5 promotes oral squamous cell carcinoma progression in the hyperosmotic environment through increased expression of DPAGT1, an essential enzyme for protein glycosylation, and altered EGFR subcellular localization from the cytoplasm to the plasma membrane in tumor cells.