SSEA3 and Sialyl Lewis a Glycan Expression Is Controlled by B3GALT5 LTR through Lamin A-NFYA and SIRT1-STAT3 Signaling in Human ES Cells

Abstract

B3GALT5 is involved in the synthesis of embryonic stem (ES) cell marker glycan, stage-specific embryonic antigen-3 (SSEA3). This gene has three native promoters and an integrated retroviral long terminal repeat (LTR) promoter. We found that B3GALT5-LTR is expressed at high levels in human ES cells. B3GALT5-LTR is also involved in the synthesis of the cancer-associated glycan, sialyl Lewis a. Sialyl Lewis a is expressed in ES cells and its expression decreases upon differentiation. Retinoic acid induced differentiation of ES cells, decreased the short form of NFYA (NFYAs), increased phosphorylation of STAT3, and decreased B3GALT5-LTR expression. NFYAs activated, and constitutively-active STAT3 (STAT3C) repressed B3GALT5-LTR promoter. The NFYAs and STAT3C effects were eliminated when their binding sites were deleted. Retinoic acid decreased the binding of NFYA to B3GALT5-LTR promoter and increased phospho-STAT3 binding. Lamin A repressed NFYAs and SSEA3 expression. SSEA3 repression mediated by a SIRT1 inhibitor was reversed by a STAT3 inhibitor. Repression of SSEA3 and sialyl Lewis a synthesis mediated by retinoic acid was partially reversed by lamin A short interfering RNA (siRNA) and a STAT3 inhibitor. In conclusion, B3GALT5-LTR is regulated by lamin A-NFYA and SIRT1-STAT3 signaling that regulates SSEA3 and sialyl Lewis a synthesis in ES cells, and sialyl Lewis a is also a ES cell marker.

Complementary Use of Carbohydrate Antigens Lewis a, Lewis b, and Sialyl-Lewis a (CA19.9 Epitope) in Gastrointestinal Cancers: Biological Rationale towards a Personalized Clinical Application

“…Notably, the glycosyltransferase pattern expressed in native tissues is available only for the colon [24,40,41,46,47] and pancreas [47][48][49], but not for other gastrointestinal organs, such as the stomach and the bile ducts (Table 1). Moreover, the available data suggest that the glycosyltransferase regulation is tissue-specific and affected by mechanisms that operate in only native tissues [28,50,51], making the studies performed in cell lines poorly representative. [47][48][49] Tissue antigens by immunofluorescence/dot-blot CA19.9, Lea, and Leb detected in both normal and cancerous ducts (luminal staining), no one in normal acinar cells or poorly differentiated cancer cells [47] Tissue antigens by immunohistochemistry CA19.9 detected in cancer (frequent cytoplasmic staining) better than in normal ducts (luminal staining) […”

“…Notably, the glycosyltransferase pattern expressed in native tissues is available only for the colon [ 24 , 40 , 41 , 46 , 47 ] and pancreas [ 47 , 48 , 49 ], but not for other gastrointestinal organs, such as the stomach and the bile ducts ( Table 1 ). Moreover, the available data suggest that the glycosyltransferase regulation is tissue-specific and affected by mechanisms that operate in only native tissues [ 28 , 50 , 51 ], making the studies performed in cell lines poorly representative.…”

“…Notably, the glycosyltransferase pattern expressed in native tissues is available only for the colon [24,40,41,46,47] and pancreas [47][48][49], but not for other gastrointestinal organs, such as the stomach and the bile ducts (Table 1). Moreover, the available data suggest that the glycosyltransferase regulation is tissue-specific and affected by mechanisms that operate in only native tissues [28,50,51], making the studies performed in cell lines poorly representative. Monosaccharides are depicted according to the current representation: Blue square, GlcNAc, N-acetylglucosamine; yellow circle, Gal, galactose; Red triangle, Fuc, fucose; Pink diamond, sialic acid, Sia.…”

Targeting glycosphingolipids for cancer immunotherapy

“…B3GALT5 is essential for the synthesis of stages specific embryonic antigen-3 (SSEA3), the pentasaccharide precursor of Globo H. This gene has three native promoters and an integrated retroviral long terminal repeat (LTR) promoter. A recent study showed that B3GALT5-LTR is regulated by lamin A-NFYA and SIRT1-STAT3 signaling [84]. Further studies are needed to explore the involvement of transcription factors in the regulation of Globo H antigen expression during tumorigenesis.…”

Homozygous deletion of 21q22.2 in a patient with hypotonia, developmental delay, cortical visual impairment, and retinopathy

“…It has been shown to act in the formation of type 1 Lewis antigens of pancreatic and colorectal epithelial cells (Isshiki et al, 1999). B3GALT5 is highly expressed in the GI tract and embryonic stem cells and to a lesser extent in the central nervous system (Cai et al, 2020). Expression levels of B3GALT5 and its lncRNAs appear to influence colon cancer metastasis and are a predictor of survival in hepatocellular carcinoma (Kuo et al, 2017; Wang et al, 2018).…”