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.