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

2.50
Hdl Handle:
http://hdl.handle.net/11287/593969
Title:
The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer
Authors:
Munkley, J.; Oltean, S.; Vodak, D.; Wilson, B. T.; Livermore, K. E.; Zhou, Y.; Star, E.; Floros, V. I.; Johannessen, B.; Knight, Bridget; McCullagh, Paul; McGrath, John S; Crundwell, Malcolm; Skotheim, R. I.; Robson, C. N.; Leung, H. Y.; Harries, L. W.; Rajan, P.; Mills, I. G.; Elliott, D. J.
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.
Citation:
Oncotarget. 2015 Oct 27;6(33):34358-74.
Publisher:
Oncotarget
Journal:
Oncotarget
Issue Date:
7-Oct-2015
URI:
http://hdl.handle.net/11287/593969
DOI:
10.18632/oncotarget.6024
PubMed ID:
26452038
Additional Links:
http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=6024
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article
Language:
eng
ISSN:
1949-2553
Appears in Collections:
2015 RD&E publications; Urology; HeSRU publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMunkley, J.en
dc.contributor.authorOltean, S.en
dc.contributor.authorVodak, D.en
dc.contributor.authorWilson, B. T.en
dc.contributor.authorLivermore, K. E.en
dc.contributor.authorZhou, Y.en
dc.contributor.authorStar, E.en
dc.contributor.authorFloros, V. I.en
dc.contributor.authorJohannessen, B.en
dc.contributor.authorKnight, Bridgeten
dc.contributor.authorMcCullagh, Paulen
dc.contributor.authorMcGrath, John Sen
dc.contributor.authorCrundwell, Malcolmen
dc.contributor.authorSkotheim, R. I.en
dc.contributor.authorRobson, C. N.en
dc.contributor.authorLeung, H. Y.en
dc.contributor.authorHarries, L. W.en
dc.contributor.authorRajan, P.en
dc.contributor.authorMills, I. G.en
dc.contributor.authorElliott, D. J.en
dc.date.accessioned2016-01-19T12:38:06Zen
dc.date.available2016-01-19T12:38:06Zen
dc.date.issued2015-10-07en
dc.identifier.citationOncotarget. 2015 Oct 27;6(33):34358-74.en
dc.identifier.issn1949-2553en
dc.identifier.pmid26452038en
dc.identifier.doi10.18632/oncotarget.6024en
dc.identifier.urihttp://hdl.handle.net/11287/593969en
dc.description.abstractPatterns 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.en
dc.language.isoengen
dc.publisherOncotargeten
dc.relation.urlhttp://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=6024en
dc.titleThe androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate canceren
dc.typeJournal Articleen
dc.identifier.journalOncotargeten
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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