The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

// Jennifer Munkley 1 , Sebastian Oltean 2 , Daniel Vodák 3 , Brian T. Wilson 1 , Karen E. Livermore 1 , Yan Zhou 5 ,Eleanor Star 2 , Vasileios I. Floros 1 , Bjarne Johannessen 6 , Bridget Knight 7 , Paul McCullagh 8 , John McGrath 9 , Malcolm Crundwell 10 , Rolf I. Skotheim 6 , Craig N. Robson 11 , Hing Y. Leung 5,12 , Lorna W. Harries 13 , Prabhakar Rajan 5,12 , Ian G. Mills 14,15,16 and David J. Elliott 1 1 Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK 2 Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK 3 Bioinformatics Core Facility, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 4 Northern Genetics Service, Newcastle Upon Tyne NHS Foundation Trust, Newcastle-upon-Tyne, UK 5 Beatson Institute for Cancer Research, Glasgow, UK 6 Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 7 NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 8 Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 9 Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 10 Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 11 Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK 12 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK 13 Institute of Biomedical and Clinical Sciences, University of Exeter, Devon, UK 14 Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), University of Oslo and Oslo University Hospitals, Oslo, Norway 15 Departments of Molecular Oncology, Institute of Cancer Research and Radium Hospital, Oslo, Norway 16 PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University, Belfast, UK Correspondence to: Jennifer Munkley, email: // Keywords : androgens, prostate cancer, ST6GalNAc1, glycosylation, Sialyl-Tn (sTn) Received : September 02, 2015 Accepted : September 09, 2015 Published : October 07, 2015 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.