Abstract
The expression of gangliosides is often associated with cancer progression. Sialyltransferases have received much attention in terms of their relationship with cancer because they modulate the expression of gangliosides. We previously demonstrated that GD1a production was high in castration-resistant prostate cancer cell lines, PC3 and DU145, mainly due to their high expression of β-galactoside α2,3-sialyltransferase (ST3Gal) II (not ST3Gal I), and the expression of both ST3Gals was regulated by NF-κB, mainly by RelB. We herein demonstrate that GD1a was produced in abundance in cancerous tissue samples from human patients with hormone-sensitive prostate cancers as well as castration-resistant prostate cancers. The expression of ST3Gal II was constitutively activated in castration-resistant prostate cancer cell lines, PC3 and DU145, because of the hypomethylation of CpG island in its promoter. However, in androgen-depleted LNCap cells, a hormone-sensitive prostate cancer cell line, the expression of ST3Gal II was silenced because of the hypermethylation of the promoter region. The expression of ST3Gal II in LNCap cells increased with testosterone treatment because of the demethylation of the CpG sites. This testosterone-dependent ST3Gal II expression was suppressed by RelB siRNA, indicating that RelB activated ST3Gal II transcription in the testosterone-induced demethylated promoter. Therefore, in hormone-sensitive prostate cancers, the production of GD1a may be regulated by androgen. This is the first report indicating that the expression of a sialyltransferase is transcriptionally regulated by androgen-dependent demethylation of the CpG sites in its gene promoter.
Highlights
Many cancer cells have aberrant sialylated glycans on their surface
Analyses of gangliosides in cancerous tissue samples from patients with prostate cancer We previously demonstrated that GD1a was abundant in castration-resistant prostate cancer cell lines, while it was barely detectable in a hormone-sensitive prostate cancer cell line (LNCap) and a normal prostate epithelial cell line (PNT2) [17]
We previously reported that ST3Gal I was expressed in LNCap cells, while the expression of ST3Gal II was silenced [20]
Summary
Many cancer cells have aberrant sialylated glycans on their surface. Sialylated glycans are synthesized by sialyltransferases, which add sialic acids to the oligosaccharide chains of glycoproteins and glycosphingolipids (GSLs) [5]. During neoplastic transformation and cancer progression, the activity of sialyltransferases is often altered, and cancer cells have more heavily sialylated glycans on their surface than noncancer cells [1,2,7]. GD1a may be involved in cancer cell proliferation and metastasis. This ganglioside is a receptor for the Sendai virus [16], and inactivated Sendai virus particles [hemagglutinating virus of Japan envelope (HVJ-E)] induce apoptosis in several human cancer cells with enriched GD1a on their surface [17]. GD1a may be an attractive molecule from the viewpoint of cancer therapy
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