Hypoxia inducible factor 1α down regulates cell surface expression of α1,2‐fucosylated glycans in human pancreatic adenocarcinoma cells

Abstract

Edited by Veli-Pekka LehtoKeywords: Glycosyltransferase Regulation of gene expression Fucosyltransferase Hypoxia inducible factor 1 a (HIF-1a) Cancer a b s t r a c tThe a1,2-fucosyltransferase activity in pancreatic tumors is much lower compared to normal pancreatic tissue. Here we show that hypoxia inducible factor (HIF) 1a is constitutively expressed in the pancreatic cancer cell lines Pa-Tu-8988S and Pa-Tu-8988T and suppresses the expression of the a1,2-fucosyltransferase genes FUT1 and FUT2. Down regulation of HIF-1a expression resulted in elevated FUT1 and FUT2 transcript levels and an increased expression of a1,2-fucosylated glycan structures on the surface of these cells. In conclusion, our data are the first to identify HIF-1a as a suppressor of FUT1/2 expression, thereby regulating a1,2-fucosylation of cell-surface glycans.

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…A study demonstrated that HIF-1α negatively regulated the fucosyltranferase expression (FUT1 and FUT2) in pancreatic cancer cell lines, resulting in low expression of fucosylated glycans on the cell surface [84]. These enzymes catalyze the addition of fucose to the galactose residues in Galβ1–3GlcNAc-R and Galβ1-4GlcNAc-R glycans to produce H type 1 and 2 antigens, respectively, precursor structures of the Blood Group A and B antigens.…”

“…These enzymes catalyze the addition of fucose to the galactose residues in Galβ1–3GlcNAc-R and Galβ1-4GlcNAc-R glycans to produce H type 1 and 2 antigens, respectively, precursor structures of the Blood Group A and B antigens. The reduction of α1,2-fucosylation results in low H-antigen levels, and, thereafter, in low levels of BG antigens, which has been associated with increased cellular motility and resistance to apoptosis [84]. However, prostate cells (RWPE1) cultured in acute hypoxia demonstrated significant upregulation of FUT1, GCNT2, and GCNT3 (Polylactosamine Branching N-Acetylglucosaminyltransferases 2 and 3), which are required for prostate cancer lipid antigen (PCLA) synthesis [69].…”

“…In colon cancer (SW480), the expressions of FUT7, ST3Gal1 (β-galactoside α-2,3-sialytransferase), and UDP-Gal transporter were induced by hypoxia [84]. FUT7 and ST3GAL1 attach fucose in α1-3 linkage to LacNAc moieties, and catalyze the transfer of N-Acetylneuraminic acid in α2-3 on Gal residues, respectively [86, 87].…”

“…FUT7 and ST3GAL1 attach fucose in α1-3 linkage to LacNAc moieties, and catalyze the transfer of N-Acetylneuraminic acid in α2-3 on Gal residues, respectively [86, 87]. These enzymes are involved in the synthesis of pro-tumor antigens sialyl Lewis x (sialyl-Le x ) and sialyl Lewis a (sialyl-Le a ), carbohydrate ligands of endothelial E-selectin, which contributes to hematogenous metastasis [84]. Sialyl-Le x and its isomer, sialyl-Le a , are tetrassacharide structures and fucosylated antigens terminated by α2-3-sialic acid linked to the galactose residues [88].…”

“…The authors reported that hypoxic conditions increased syndecan-4 and α5-integrin gene expression. Both macromolecules are involved in cellular migration and cell-adhesion processes, especially in the enhanced adhesion of cancer cells to fibronectin, which is considerably expressed by vascular endothelial cells [84]. …”