Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA912121 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22730800.fastq.gz | Fastqsanger.gz | |||
| SRR22730801.fastq.gz | Fastqsanger.gz | |||
| SRR22730802.fastq.gz | Fastqsanger.gz | |||
| SRR22730803.fastq.gz | Fastqsanger.gz | |||
| SRR22730804.fastq.gz | Fastqsanger.gz |
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Project description:Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion. One of the key drivers of aberrant glycosylation is the dysregulated expression of glycosylation enzymes within the cancer cell. Here, we demonstrate using multiple independent clinical cohorts that the glycosyltransferase enzyme GALNT7 is upregulated in prostate cancer tissue. We show GALNT7 can identify men with prostate cancer, using urine and blood samples, with improved diagnostic accuracy than serum PSA alone. We also show that GALNT7 levels remain high in progression to castrate-resistant disease, and using in vitro and in vivo models, reveal that GALNT7 promotes prostate tumour growth. Mechanistically, GALNT7 can modify O-glycosylation in prostate cancer cells and correlates with cell cycle and immune signalling pathways. Our study provides a new biomarker to aid the diagnosis of clinically significant disease and cements GALNT7-mediated O-glycosylation as an important driver of prostate cancer progression.
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Project description:This project was done in collaboration with Dr. Richard Cummings to examine sialylation of CD44v6 and its role in clearance of neutrophils from inflamed intestinal epithelium. Specifically, we have employed a functional approach using membrane preparations from interferon gamma-stimulated intestinal epithelial cells to generate a monoclonal antibody, designated GM35, which blocks neutrophil transepithelial migration through the promotion of neutrophil adhesion at the apical surface of the intestinal epithelium. Protein biochemistry, sequencing, confocal microscopic analysis, and immunoprecipitation studies all identify the protein ligand for this antibody as CD44v6. However, selective inhibition of O- or N-linked glycosylation reveal that the antibody is specific for an O-linked glycotope and glycoarray analysis of the GM35 antibody by Core H of the Consortium for Functional Glycomics reveal that this antibody binds with high affinity and specificity to a carbohydrate epitope consistent in structure with sLeA. Inhibition of O-linked glycosylation attenuated both GM35 binding and its functional effects as did specific cleavage of sialic acid residues from the cell surface, using neuraminidase, although the functional effects of cleavage were smaller and harder to assess. CD44v6 has previously been studied as a marker of inflammation in Inflammatory Bowel Disease, and GM35 staining is clearly upregulated by interferon gamma in T84 and HT29 intestinal epithelial cells. The specific enzymes governing the sialylation of CD44v6 in intestinal epithelium have yet to be determined. Analysis of a panel of intestinal epithelial cells including T84, HT29, and Caco-2 cells revealed that cell-type specific regulation of both splicing and glycosylation is essential for the regulation of the expression of the GM35 epitope. And, forcible expression of CD44 in Caco-2 cells, which are negative for CD44v6 at baseline, results only in upregulation of previously expressed isoforms of CD44, but not in GM35 expression. Based on western blot and immunofluorescent staining, GM35 expression is greatest in interferon gamma-treated T84 cells. Thus, we analyzed RNA samples for the expression of glycosylation specific genes in interferon gamma-stimulated T84 cells relative to that of both non-stimulated T84 cells and GM35-negative Caco-2 cells in order to identify glycosylation-specific targets contributing to the interferon gamma-dependent upregulation of sialylated CD44v6 in intestinal epithelial cells.
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