Epigenetic silencing of the synthesis of immunosuppressive Siglec ligand glycans by NF-κB/EZH2/YY1 axis in early-stage colon cancers

Abstract

Normal colonic epithelial cells express sialyl 6-sulfo Lewisx and disialyl Lewisa on their cell surface, which are ligands for the immunosuppressive molecule Siglec-7. Expression of these normal glycans is frequently lost upon malignant transformation by silencing DTDST and ST6GalNAc6 at the early stage of colorectal carcinogenesis, and leads to production of inflammatory mediators that facilitate carcinogenesis.Indeed, by querying The Cancer Genome Atlas datasets, we confirmed that the level of DTDST or ST6GalNAc6 mRNA is substantially decreased at the early stage of colorectal carcinogenesis. Cultured colon cancer cell lines were used in this study including DLD-1, HT-29, LS174T and SW620. Their promoter regions were strongly marked by repressive mark H3K27me3, catalyzed by EZH2 that was markedly upregulated in early stage of colorectal carcinogenesis. Suppression of EZH2 substantially downregulated H3K27me3 mark and upregulated DTDST and ST6GalNAc6 as well as expression of normal glycans and Siglec-binding activities.Transcription factor YY1 was vital for the recruitment of PRC2-containing EZH2 to both promoters. Inhibition of NF-κB substantially reduced EZH2 transcription and restored their mRNAs as well as the production of normal Siglec ligand glycans in the results obtained from in vitro studies on cultured colon cancer cell lines.These findings provide a putative mechanism for promotion of carcinogenesis by loss of immunosuppressive molecules by epigenetic silencing through NF-κB-mediated EZH2/YY1 axis.