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Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

ABSTRACT: 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.

SUBMITTER: Scott E

PROVIDER: S-EPMC10020086 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

Scott Emma E Hodgson Kirsty K Calle Beatriz B Turner Helen H Cheung Kathleen K Bermudez Abel A Marques Fernando Jose Garcia FJG Pye Hayley H Yo Edward Christopher EC Islam Khirul K Oo Htoo Zarni HZ McClurg Urszula L UL Wilson Laura L Thomas Huw H Frame Fiona M FM Orozco-Moreno Margarita M Bastian Kayla K Arredondo Hector M HM Roustan Chloe C Gray Melissa Anne MA Kelly Lois L Tolson Aaron A Mellor Ellie E Hysenaj Gerald G Goode Emily Archer EA Garnham Rebecca R Duxfield Adam A Heavey Susan S Stopka-Farooqui Urszula U Haider Aiman A Freeman Alex A Singh Saurabh S Johnston Edward W EW Punwani Shonit S Knight Bridget B McCullagh Paul P McGrath John J Crundwell Malcolm M Harries Lorna L Bogdan Denisa D Westaby Daniel D Fowler Gemma G Flohr Penny P Yuan Wei W Sharp Adam A de Bono Johann J Maitland Norman J NJ Wisnovsky Simon S Bertozzi Carolyn R CR Heer Rakesh R Guerrero Ramon Hurtado RH Daugaard Mads M Leivo Janne J Whitaker Hayley H Pitteri Sharon S Wang Ning N Elliott David J DJ Schumann Benjamin B Munkley Jennifer J

Oncogene 20230201 12

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 enzyme ...[more]

PMID: 36725887

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Project description:ObjectivesReprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose-dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration-resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown.Materials and methodsLoss-of-function and gain-of-function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real-time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms.ResultsPRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss-of-function and gain-of-function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia-inducible factor 1α (HIF-1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF-1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B-mediated tumour-promoting effect. Similar phenomenon was noticed by genetic silencing of HIF-1α.ConclusionsOur study identified that PRKAR2B-HIF-1α loop enhances the Warburg effect to enable growth advantage in prostate cancer.

Dataset Information

Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

Publications

Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

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