title: The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer.
abstract: Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Munkley
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Oltean
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: Vodák
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wilson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Livermore
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Star
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Vasileios I
authors.initials: VI
authors.lastname: Floros
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Johannessen
authors.affiliation: NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Bridget
authors.initials: B
authors.lastname: Knight
authors.affiliation: Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: McCullagh
authors.affiliation: Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, 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: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter, Devon, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Rajan
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: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Elliott
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis*; D002448:Cell Adhesion / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012799:Sialyltransferases / Q000378:metabolism*; D014162:Transfection; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D015295:Antigens, Tumor-Associated, Carbohydrate; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012799:Sialyltransferases; C055491:sialosyl-Tn antigen; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
keywords: ST6GalNAc1; Sialyl-Tn (sTn); androgens; glycosylation; prostate cancer