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

Gliomas 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 the ETS1 promoter 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 Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for p52 and ETS1 in control and ETS1 knockdown U-87 MG cells, with and without TWEAK stimulation Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for RNApol2 in control, ETS1 and NFKB2 knockdown U-87 MG cells, with and without TWEAK stimulation RNA-sequencing on control untreated, control TWEAK treated, ETS1 knockdown TWEAK treated and NFKB2 knockdown TWEAK treated U87-MG cells