Suppression of the expression of sulfated poly-LacNAc chain-related genes in colon cancer
Date Issued
2015
Date
2015
Author(s)
Wu, Min-Hui
Abstract
Poly-LacNAc chain, composed of repeating disaccharide unit of N-acetyllactosamine (LacNAc), is one of the major glyco-structures on the cell surface. The sixth carbon positions (C-6) of the Gal and GlcNAc residues of the poly-LacNAc chains can be sulfated, through the activities of carbohydrate (keratan sulfate Gal-6) sulfotransferase 1 (CHST1) and carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6 (CHST6), respectively, and this transforms the chains into sulfated poly-LacNAc chains. It has been shown that β-1,3-N-acetylglucosaminyltransferase 7 (B3GNT7) and β-1,4-galactosyltransferase 4 (B4GALT4) are responsible for the elongation of sulfated poly-LacNAc chains. In addition, the UDP-GlcNAc transporter, solute carrier family 35, member A3 (SLC35A3) has been shown to be involved in the biosynthesis of sulfated poly-LacNAc chains. The sialyl Lewis a (sLea) and sialyl Lewis x (sLex) glyco-antigens are constructed on the terminals of poly-LacNAc chains. They have been show to play a critical role during carcinogenesis of gastrointestinal cancers, and are well-known tumor-associated carbohydrate antigens. Our recent investigation demonstrated that B3GNT7 gene was significantly down-regulated, through promoter DNA methylation, in colon tumor tissue. Ectopic expression of B3GNT7 gene in colon cancer cell line suppressed the expression of sLea antigen and reduced the metastasis capability of the cells. Based on these previous findings, we aim to further analyze the expression profile of the other four sulfated poly-LacNAc chain-related genes, CHST1, CHST6, B4GALT4 and SLC35A3, during colon cancer oncogenesis. The result showed that the expression of CHST1 and CHST6 genes did not show a consistent up- or down-regulation pattern in colon tumor tissues, while the expression of B4GALT4 and SLC35A3 genes are significantly down-regulated in tumor tissues. Ectopic expression of the B4GALT4 gene in HT-29 colon cancer cells leads to a reduction in the expression of sLea and sLex antigens on cell surfaces. However, the results obtained from bisulfite sequencing showed that the suppression of the B4GALT4 and SLC35A3 genes in colon tumors were not due to promoter DNA methylation. To explore the epigenetic mechanism leading to the suppression of these genes, we treated colon cancer cells with various epigenetic drugs. Interestingly, the data show that DNA methylation inhibitor 5-aza-2’-deoxycytidine markedly induced the expression of both genes in colon cancer cells, suggesting that unidentified mechanism are directly or indirectly involved in the regulation of B4GALT4 and SLC35A3 genes during colon cancer oncogenesis. In future investigations, we plan to investigate the mechanism involved in the suppression of B4GALT4 and SLC35A3 and the functional roles of the expression of sulfated poly-LacNAc chains in the suppression of sLea and sLex antigens in colon cancer.
Subjects
colon cancer
metastasis
tumor-associated antigen
DNA methylation inhibitor
HDAC inhibitor
SDGs
Type
thesis
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