ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

Emma Scott; Emily Archer Goode; Rebecca Garnham; Kirsty Hodgson; Margarita Orozco-Moreno; Helen Turner; Karen Livermore; Kyla Putri Nangkana; Fiona M Frame; Abel Bermudez; Fernando Jose Garcia Marques; Urszula L McClurg; Laura Wilson; Huw Thomas; Adriana Buskin; Anastasia Hepburn; Adam Duxfield; Kayla Bastian; Hayley Pye; Hector M Arredondo; Gerald Hysenaj; Susan Heavey; Urszula Stopka-Farooqui; Aiman Haider; Alex Freeman; Saurabh Singh; Edward W Johnston; Shonit Punwani; Bridget Knight; Paul McCullagh; John McGrath; Malcolm Crundwell; Lorna Harries; Rakesh Heer; Norman J Maitland; Hayley Whitaker; Sharon Pitteri; Dean A Troyer; Ning Wang; David J Elliott; Richard R Drake; Jennifer Munkley

doi:10.1002/path.6152

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

Emma Scott, Emily Archer Goode, Rebecca Garnham, Kirsty Hodgson, Margarita Orozco-Moreno, Helen Turner, Karen Livermore, Kyla Putri Nangkana, Fiona M Frame, Abel Bermudez, Fernando Jose Garcia Marques, Urszula L McClurg, Laura Wilson, Huw Thomas, Adriana Buskin, Anastasia Hepburn, Adam Duxfield, Kayla Bastian, Hayley Pye, Hector M ArredondoGerald Hysenaj, Susan Heavey, Urszula Stopka-Farooqui, Aiman Haider, Alex Freeman, Saurabh Singh, Edward W Johnston, Shonit Punwani, Bridget Knight, Paul McCullagh, John McGrath, Malcolm Crundwell, Lorna Harries, Rakesh Heer, Norman J Maitland, Hayley Whitaker, Sharon Pitteri, Dean A Troyer, Ning Wang, David J Elliott, Richard R Drake, Jennifer Munkley

Research output: Contribution to journal › Article › peer-review

Abstract

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3F AX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Original language	English
Pages (from-to)	71-84
Number of pages	14
Journal	Journal of Pathology
Volume	261
Issue number	1
Early online date	7 Aug 2023
DOIs	https://doi.org/10.1002/path.6152
Publication status	Published - 30 Aug 2023

Bibliographical note

Keywords

Male
Humans
Sialyltransferases
Prostatic Neoplasms
Glycosylation
Polysaccharides/chemistry
United Kingdom
beta-D-Galactoside alpha 2-6-Sialyltransferase
Antigens, CD/metabolism

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10.1002/path.6152Licence: CC BY

Cite this

Scott, E., Archer Goode, E., Garnham, R., Hodgson, K., Orozco-Moreno, M., Turner, H., Livermore, K., Putri Nangkana, K., Frame, F. M., Bermudez, A., Jose Garcia Marques, F., McClurg, U. L., Wilson, L., Thomas, H., Buskin, A., Hepburn, A., Duxfield, A., Bastian, K., Pye, H., ... Munkley, J. (2023). ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression. Journal of Pathology, 261(1), 71-84. https://doi.org/10.1002/path.6152

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title = "ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression",

abstract = "Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3F AX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. {\textcopyright} 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. ",

keywords = "Male, Humans, Sialyltransferases, Prostatic Neoplasms, Glycosylation, Polysaccharides/chemistry, United Kingdom, beta-D-Galactoside alpha 2-6-Sialyltransferase, Antigens, CD/metabolism",

author = "Emma Scott and {Archer Goode}, Emily and Rebecca Garnham and Kirsty Hodgson and Margarita Orozco-Moreno and Helen Turner and Karen Livermore and {Putri Nangkana}, Kyla and Frame, {Fiona M} and Abel Bermudez and {Jose Garcia Marques}, Fernando and McClurg, {Urszula L} and Laura Wilson and Huw Thomas and Adriana Buskin and Anastasia Hepburn and Adam Duxfield and Kayla Bastian and Hayley Pye and Arredondo, {Hector M} and Gerald Hysenaj and Susan Heavey and Urszula Stopka-Farooqui and Aiman Haider and Alex Freeman and Saurabh Singh and Johnston, {Edward W} and Shonit Punwani and Bridget Knight and Paul McCullagh and John McGrath and Malcolm Crundwell and Lorna Harries and Rakesh Heer and Maitland, {Norman J} and Hayley Whitaker and Sharon Pitteri and Troyer, {Dean A} and Ning Wang and Elliott, {David J} and Drake, {Richard R} and Jennifer Munkley",

note = "{\textcopyright} 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.",

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doi = "10.1002/path.6152",

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volume = "261",

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Scott, E, Archer Goode, E, Garnham, R, Hodgson, K, Orozco-Moreno, M, Turner, H, Livermore, K, Putri Nangkana, K, Frame, FM, Bermudez, A, Jose Garcia Marques, F, McClurg, UL, Wilson, L, Thomas, H, Buskin, A, Hepburn, A, Duxfield, A, Bastian, K, Pye, H, Arredondo, HM, Hysenaj, G, Heavey, S, Stopka-Farooqui, U, Haider, A, Freeman, A, Singh, S, Johnston, EW, Punwani, S, Knight, B, McCullagh, P, McGrath, J, Crundwell, M, Harries, L, Heer, R, Maitland, NJ, Whitaker, H, Pitteri, S, Troyer, DA, Wang, N, Elliott, DJ, Drake, RR & Munkley, J 2023, 'ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression', Journal of Pathology, vol. 261, no. 1, pp. 71-84. https://doi.org/10.1002/path.6152

TY - JOUR

T1 - ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

AU - Scott, Emma

AU - Archer Goode, Emily

AU - Garnham, Rebecca

AU - Hodgson, Kirsty

AU - Orozco-Moreno, Margarita

AU - Turner, Helen

AU - Livermore, Karen

AU - Putri Nangkana, Kyla

AU - Frame, Fiona M

AU - Bermudez, Abel

AU - Jose Garcia Marques, Fernando

AU - McClurg, Urszula L

AU - Wilson, Laura

AU - Thomas, Huw

AU - Buskin, Adriana

AU - Hepburn, Anastasia

AU - Duxfield, Adam

AU - Bastian, Kayla

AU - Pye, Hayley

AU - Arredondo, Hector M

AU - Hysenaj, Gerald

AU - Heavey, Susan

AU - Stopka-Farooqui, Urszula

AU - Haider, Aiman

AU - Freeman, Alex

AU - Singh, Saurabh

AU - Johnston, Edward W

AU - Punwani, Shonit

AU - Knight, Bridget

AU - McCullagh, Paul

AU - McGrath, John

AU - Crundwell, Malcolm

AU - Harries, Lorna

AU - Heer, Rakesh

AU - Maitland, Norman J

AU - Whitaker, Hayley

AU - Pitteri, Sharon

AU - Troyer, Dean A

AU - Wang, Ning

AU - Elliott, David J

AU - Drake, Richard R

AU - Munkley, Jennifer

PY - 2023/8/30

Y1 - 2023/8/30

N2 - Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3F AX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

AB - Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3F AX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

KW - Male

KW - Humans

KW - Sialyltransferases

KW - Prostatic Neoplasms

KW - Glycosylation

KW - Polysaccharides/chemistry

KW - United Kingdom

KW - beta-D-Galactoside alpha 2-6-Sialyltransferase

KW - Antigens, CD/metabolism

U2 - 10.1002/path.6152

DO - 10.1002/path.6152

M3 - Article

C2 - 37550801

SN - 0022-3417

VL - 261

SP - 71

EP - 84

JO - Journal of Pathology

JF - Journal of Pathology

IS - 1

ER -