title: Glycosylation is an Androgen-Regulated Process Essential for Prostate Cancer Cell Viability.
abstract: Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl Lewis(X) (SLe(X)), O-GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. Electronic address: jennifer.munkley@ncl.ac.uk.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Munkley
authors.affiliation: Bioinformatics Core Facility, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vodak
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Livermore
authors.affiliation: Interdisciplinary Computing and Complex BioSystems Research Group, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: James
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Northern Genetics Service, Newcastle Upon Tyne NHS Foundation Trust, International Centre for Life, Newcastle upon Tyne, UK.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wilson
authors.affiliation: NIHR Exeter Clinical Research Facility, RD&E NHS Foundation Trust, UK.
authors.forename: Bridget
authors.initials: B
authors.lastname: Knight
authors.affiliation: Department of Pathology, RD&E NHS Foundation Trust, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Mccullagh
authors.affiliation: Exeter Surgical Health Services Research Unit, RD&E NHS Foundation Trust, UK.
authors.forename: John
authors.initials: J
authors.lastname: Mcgrath
authors.affiliation: Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Crundwell
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter, Devon EX1 2LU, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), University of Oslo and Oslo University Hospitals, Oslo, Norway; Departments of Molecular Oncology, Institute of Cancer Research and Radium Hospital, Oslo, Norway; PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University, Belfast, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Rajan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Elliott
mesh_terms: D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003871:Dermatan Sulfate / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000728:Androgens; D003871:Dermatan Sulfate