FAS gene, a direct target for NFκB transcription factor, is repressed in solid tumors including colon carcinomas. We have previously reported that, while overexpressed in low risk myelodysplastic syndromes (MDS), the Fas death receptor becomes undetectable on CD34 + progenitors when the disease progresses to secondary acute myeloid leukaemia (sAML). This study aimed at investigating the interplay between NFκB and Fas during MDS progression.We first observed that Fas was inducible by TNFα in the HL60 cell line. In these cells, p65/RelA bound to the chromatin at FAS promoter, while inhibition of NFκB pathway by IKKα inhibitor BAY11-7082 or lentiviral expression of a non-degradable mutant of IκBα, IκSR blocked the expression of Fas. By contrast, TNFα failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. In vitro use of azacitidine rescued p65/RelA binding on FAS promoter and, subsequently Fas expression in SW480 cells. We also show that, inhibition of NFκB pathway decreased the expression of Fas in MDS CD45 lo CD34 + bone marrow cells. However, despite of the nuclear expression of p65/RelA, Fas was often low on CD45 lo CD34 + AML cells. TNFα failed to stimulate its expression, while azacitidine efficiently rescued p65/RelA binding and Fas reexpression. Our data suggest that DNA methylation at NFκB sites is responsible for FAS gene silencing. Rescuing FAS gene expression by azacitidine could contribute to slacken the progression to leukaemia.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.