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

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

doi:10.1038/s41467-020-19575-2

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.

Highlights

Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease
Grouping of genes into enrichment clusters revealed by DAVID functional annotation tool identified O-Glycan biosynthesis pathway (p = 5.9E-3) among the top-7 pathways significantly downregulated in both SOX2-and GLI1depleted melanoma cells (Fig. 1c)
RNA-seq results coupled with quantitative real-time polymerase chain reaction (PCR) validation identified six different glycosyltransferases significantly downregulated in both SOX2- and GLI1-silenced cells: the N-acetylgalactosaminyltransferases GALNT3, GALNT6 and GALNT12, the sialyltransferase ST3GAL1 and the N-acetylglucosaminyltransferases GCNT1 and GCNT2 (Fig. 1d–f)

Summary

Introduction

Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Identification and targeting of key drivers of melanoma metastasis are crucial steps towards an effective control of tumor progression. In particular increased sialylation, is an important determinant of malignant phenotype, as it directly impacts on key processes supporting tumor progression and metastasis, including cell adhesion, motility, invasion, and immune evasion[2,3,4,5,6,7]. Using in vitro and in vivo assays, we demonstrate that ST3GAL1, a β-galactoside-α-2,3-sialyltransferase-1 that catalyzes the transfer of sialic acid from cytidine monosphosphate (CMP)sialic acid to galactose-containing substrates, is a crucial driver of melanoma invasion and metastasis downstream the SOX2-GLI1 transcriptional complex. Biochemical and functional studies reveal that the receptor tyrosine kinase AXL is a major mediator of the pro-invasive effects of ST3GAL1 in melanoma. Our study reveals a functional ST3GAL1-AXL axis driving melanoma metastasis and suggests that inhibition of this axis may become in the future a promising therapeutic strategy for metastatic melanoma

Methods

Results

Conclusion