Abstract
Simple SummaryThe carbohydrate moiety of cell surface glycolipids is modified in cancers of neuro–ectoderm origin, leading to the expression of more complex structures with two or more sialic acid residues. These alterations result from the upregulation of the ST8SIA1 gene that encodes GD3 synthase, the enzyme controlling the biosynthesis of complex gangliosides, and are usually associated with a more aggressive phenotype and a poor outcome for patients, making GD3 synthase an interesting target for cancer therapy. This review reports our general knowledge of GD3 synthase gene expression and regulation, its role in both epithelial–mesenchymal transition (EMT) and cancer progression, and the different approaches targeting GD3S expression in cancers.GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuro–ectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelial–mesenchymal transition. Since GD3 and GD2 levels are directly linked to GD3 synthase expression and activity, targeting GD3 synthase appears to be a promising strategy through which to interfere with ganglioside-associated malignant properties. We review here the current knowledge on GD3 synthase expression and regulation in cancers, and the consequences of complex ganglioside expression on cancer cell signaling and properties, highlighting the relationships between GD3 synthase expression and epithelial–mesenchymal transition and stemness. Different strategies were used to modulate GD3 synthase expression in cancer cells in vitro and in animal models, such as inhibitors or siRNA/lncRNA, which efficiently reduced cancer cell malignant properties and the proportion of GD2 positive cancer stem cells, which are associated with high metastatic properties, resistance to therapy, and cancer relapse. These data show the relevance of targeting GD3 synthase in association with conventional therapies, to decrease the number of cancer stem cells in tumors.
Highlights
ST8SIA1 Gene Expression and Regulation in CancersThe ST8SIA1 gene encoding GD3 synthase (GD3S) is localized on chromosome 12 (p12.1–p11.2 locus). It is composed of five coding exons, spanning over 135 kbp [30]
Introduction iationsChanges in glycosylation is a common feature of cancer cells that affects both N- and Oglycosylproteins as well as glycophingolipids, leading to the expression of tumor-associated carbohydrate antigens (TACA)
We summarize our current knowledge on GD3 synthase expression and regulation in cancers, its role in cancer progression and metastasis, as well as in EMT and stemness properties
Summary
The ST8SIA1 gene encoding GD3S is localized on chromosome 12 (p12.1–p11.2 locus). It is composed of five coding exons, spanning over 135 kbp [30]. The promoter region of the ST8SIA1 gene has been studied in various cell types, such as melanoma [30,36], glioblastoma [37], neuroblastoma [38], and breast cancer cell lines [39]. In SK MEL-2 melanoma cells, the promoter region lacks TATA and CAAT boxes, but contains putative binding sites for general transcription factors associated with cancers contains putative binding sites for general transcription factors associated with cancers and inflammation (c-Ets-1, CREB, AP-1, NF-κB), with a crucial role of NF-κB in ST8SIA1 and inflammation (c-Ets-1, CREB, AP-1, NF-κB), with a crucial role of NF-κB in ST8SIA1 expression in SK-MEL-2 cells (Figure 1). ERα positive breast cancer cells, binding site critical for promoter activity. ST8SIA1 cancer cell lines and tissues tested [42] Another mechanism of ST8SIA1 regulation regulation involves non-coding. A better understanding of the multiple control levels of GD3S expression, the enzyme that controls GD3 and GD2 ganglioside expression, is key for defining new therapeutic strategies to decrease cancer cell malignant properties
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