Abstract
Recent data have underlined a possible role of GD3 synthase (GD3S) and complex gangliosides in Estrogen Receptor (ER) negative breast cancer progression. Here, we describe the main transcript of the GD3S coding gene ST8SIA1 expressed in breast tumors. We characterized the corresponding core promoter in Hs578T breast cancer cells and showed that estradiol decreases ST8SIA1 mRNA expression in ER-positive MCF-7 cells and ERα-transfected ER-negative Hs578T cells. The activity of the core promoter sequence of ST8SIA1 is also repressed by estradiol. The core promoter of ST8SIA1 contains two putative Estrogen Response Elements (ERE) that were not found to be involved in the promoter activity pathway. However, NFκB was shown to be involved in ST8SIA1 transcriptional activation and we demonstrated that estradiol prevents NFκB to bind to ST8SIA1 core promoter in ERα expressing breast cancer cells by inhibiting p65 and p50 nucleus localization. The activation of NFκB pathway in ER-negative tumors, due to the absence of estradiol signaling, might explain the overexpression of GD3 synthase in this tumor subtype.
Highlights
Gangliosides are glycosphingolipids carrying one or several sialic acid residues, and are essential compounds of the plasma membrane, by exposing their glycan moiety to the extracellular domain
The 59-UTR of ST8SIA1 transcripts were previously reported in melanoma, glioblastoma and neuroblastoma cell lines, showing a unique transcript, called T1, with several transcription start sites (TSS) within the first exon E1, from 2400 to 2650 bp upstream the ATG [24,25,26,27]. 59-UTR amplification was performed for Hs578T cells and 3 tumor samples representative of the different levels of ST8SIA1 expression (#137, #142 and #144) by 59-Rapid Amplification of cDNA Ends (59-RACE) as described in the Material and Methods section (Fig. 1A)
We determined that T1 is the major transcript of GD3 synthase (GD3S) expressed in breast tumor tissues and we characterized the core promoter essential for transcription of GD3S in human breast cancer cells
Summary
Gangliosides are glycosphingolipids carrying one or several sialic acid residues, and are essential compounds of the plasma membrane, by exposing their glycan moiety to the extracellular domain. They are enriched together with other phospholipids and cholesterol in lipid microdomains named ‘‘glycosynapses’’, where they can modulate cell signaling, leading to changes in cellular phenotype [1,2]. Complex gangliosides such as GD3, GT3 or GD2 have been found over-expressed in human tumors of neuroectoderm origin such as melanoma, glioblastoma and neuroblastoma [7,8,9] They play a functional role in tumor growth and metastasis by mediating cell proliferation, migration, adhesion and angiogenesis [10]. Complex gangliosides have been used as target molecules for cancer immunotherapy, such as GD3 in melanoma [11,12] and GD2 in neuroblastoma [13,14]
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