ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

Silvia Pietrobono; Giulia Anichini; Cesare Sala; Fabrizio Manetti; Luciana L. Almada; Sara Pepe; Ryan M. Carr; Brooke D. Paradise; Jann N. Sarkaria; Jaime I. Davila; Lorenzo Tofani; Ilaria Battisti; Giorgio Arrigoni; Li Ying; Cheng Zhang; Hu Li; Alexander Meves; Martin E. Fernandez-Zapico; Barbara Stecca

doi:10.1038/s41467-020-19575-2

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

Silvia Pietrobono, Giulia Anichini, Cesare Sala, Fabrizio Manetti, Luciana L. Almada, Sara Pepe, Ryan M. Carr, Brooke D. Paradise, Jann N. Sarkaria, Jaime I. Davila, Lorenzo Tofani, Ilaria Battisti, Giorgio Arrigoni, Li Ying, Cheng Zhang, Hu Li, Alexander Meves, Martin E. Fernandez-Zapico, Barbara Stecca

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Abstract

Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

Original language	English (US)
Article number	5865
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19575-2
State	Published - Dec 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Pietrobono, S., Anichini, G., Sala, C., Manetti, F., Almada, L. L., Pepe, S., Carr, R. M., Paradise, B. D., Sarkaria, J. N., Davila, J. I., Tofani, L., Battisti, I., Arrigoni, G., Ying, L., Zhang, C., Li, H., Meves, A., Fernandez-Zapico, M. E., & Stecca, B. (2020). ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL. Nature communications, 11(1), Article 5865. https://doi.org/10.1038/s41467-020-19575-2

Pietrobono, S, Anichini, G, Sala, C, Manetti, F, Almada, LL, Pepe, S, Carr, RM, Paradise, BD, Sarkaria, JN, Davila, JI, Tofani, L, Battisti, I, Arrigoni, G, Ying, L, Zhang, C, Li, H , Meves, A , Fernandez-Zapico, ME & Stecca, B 2020, 'ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL', Nature communications, vol. 11, no. 1, 5865. https://doi.org/10.1038/s41467-020-19575-2

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title = "ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL",

abstract = "Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.",

author = "Silvia Pietrobono and Giulia Anichini and Cesare Sala and Fabrizio Manetti and Almada, {Luciana L.} and Sara Pepe and Carr, {Ryan M.} and Paradise, {Brooke D.} and Sarkaria, {Jann N.} and Davila, {Jaime I.} and Lorenzo Tofani and Ilaria Battisti and Giorgio Arrigoni and Li Ying and Cheng Zhang and Hu Li and Alexander Meves and Fernandez-Zapico, {Martin E.} and Barbara Stecca",

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AU - Pietrobono, Silvia

AU - Anichini, Giulia

AU - Sala, Cesare

AU - Manetti, Fabrizio

AU - Almada, Luciana L.

AU - Pepe, Sara

AU - Carr, Ryan M.

AU - Paradise, Brooke D.

AU - Sarkaria, Jann N.

AU - Davila, Jaime I.

AU - Tofani, Lorenzo

AU - Battisti, Ilaria

AU - Arrigoni, Giorgio

AU - Ying, Li

AU - Zhang, Cheng

AU - Li, Hu

AU - Meves, Alexander

AU - Fernandez-Zapico, Martin E.

AU - Stecca, Barbara

PY - 2020/12

Y1 - 2020/12

N2 - Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

AB - Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

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ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

Abstract

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