NF-κB/p52 augments ETS1 binding genome-wide to promote glioma progression

Abstract

AbstractGliomas are among the most invasive and chemo-resistant cancers, making them challenging to treat. Chronic inflammation is one of the key drivers of glioma progression as it promotes the aberrant activation of inflammatory pathways such as NF-κB signalling which drives cancer cell invasion, angiogenesis and tissue remodelling. NF-κB factors typically dimerize with its own family members, but emerging evidence of their promiscuous interactions with other oncogenic factors have been reported to activate the transcription of new target genes and function. Here, we show that non-canonical NF-κB activation directly regulates p52 at theETS1promoter to activate its expression. This in turn impacts the genomic and transcriptional landscape of ETS1 in a glioma-specific manner. We further show that enhanced non-canonical NF-κB signalling promotes the co-localization of p52 and ETS1, resulting in the transcriptional activation of non-κB and/or non-ETS glioma-promoting genes. We conclude that p52-induced ETS1 overexpression in glioma cells remodels the genome-wide regulatory network of p52 and ETS1 to transcriptionally drive cancer progression.