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 and Barbara Stecca ()
Additional contact information
Silvia Pietrobono: Core Research Laboratory – Institute for Cancer Research and Prevention (ISPRO)
Giulia Anichini: Core Research Laboratory – Institute for Cancer Research and Prevention (ISPRO)
Cesare Sala: University of Florence
Fabrizio Manetti: University of Siena
Luciana L. Almada: Mayo Clinic
Sara Pepe: Core Research Laboratory – Institute for Cancer Research and Prevention (ISPRO)
Ryan M. Carr: Mayo Clinic
Brooke D. Paradise: Mayo Clinic
Jann N. Sarkaria: Mayo Clinic
Jaime I. Davila: Mayo Clinic, Rochester
Lorenzo Tofani: University of Florence
Ilaria Battisti: University of Padova and Azienda Ospedaliera di Padova
Giorgio Arrigoni: University of Padova and Azienda Ospedaliera di Padova
Li Ying: Mayo Clinic
Cheng Zhang: Mayo Clinic
Hu Li: Mayo Clinic
Alexander Meves: Mayo Clinic
Martin E. Fernandez-Zapico: Mayo Clinic
Barbara Stecca: Core Research Laboratory – Institute for Cancer Research and Prevention (ISPRO)

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19575-2

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