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Open AccessArticle

BGN/TLR4/NF-B Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells

1
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
2
Department of Medicine, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 397; https://doi.org/10.3390/cells9020397
Received: 30 December 2019 / Revised: 6 February 2020 / Accepted: 6 February 2020 / Published: 9 February 2020
(This article belongs to the Special Issue Glycosylation and Cell Biology)
Human Toll-like receptor (TLR) signaling plays a vital role in intestinal inflammation by activating the NF-B pathway. By querying GENT2 datasets, we identified the gene expression level of TLR2 and TLR4 as being substantially increased in colorectal cancer. Introduction of shRNAs for TLR4 but not TLR2 dramatically recovered disialyl Lewisa and sialyl 6-sulfo Lewisx glycans, which are preferentially expressed in non-malignant colonic epithelial cells and could serve as ligands for the immunosuppressive molecule Siglec-7. We screened several TLR4 ligands and found that among them BGN is highly expressed in cancers and is involved in the epigenetic silencing of Siglec-7 ligands. Suppression of BGN expression substantially downregulated NF-B activity and the marker H3K27me3 in the promoter regions of the SLC26A2 and ST6GalNAc6 genes, which are involved in the synthesis of those glycans, and restored expression of normal glycans as well as Siglec-7 binding activities. We show that in the presence of TLR4, inflammatory stimuli initiate a positive loop involving NF-B that activates BGN and further enhances TLR4 activity. Present findings indicate a putative mechanism for the promotion of carcinogenesis by loss of immunosuppressive ligands by the BGN/TLR4/ NF-B pathway.
Keywords: TLR; NF-B; sialyl 6-sulfo Lewisx; disialyl Lewisa; BGN; Siglec-7; SLC26A2; ST6GalNAc6 TLR; NF-B; sialyl 6-sulfo Lewisx; disialyl Lewisa; BGN; Siglec-7; SLC26A2; ST6GalNAc6
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Huang, H.-C.; Cai, B.-H.; Suen, C.-S.; Lee, H.-Y.; Hwang, M.-J.; Liu, F.-T.; Kannagi, R. BGN/TLR4/NF-B Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells. Cells 2020, 9, 397.

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