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The Cancer Genome Atlas TCGA network study of 12 cancer types PanCancer 12 revealed frequent mutation of TP53 and amplification and expression of related TP63 isoform Np63 in squamous cancers Further aberrant expression of inflammatory genes and TP53 p63 p73 targets were detected in the PanCancer 12 project reminiscent of gene programs comodulated by cREL Np63 TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas HNSCCs However how inflammatory gene signatures and cREL p63 p73 targets are comodulated genome wide is unclear Here we examined how the inflammatory factor tumor necrosis factor- TNF- broadly modulates redistribution of cREL with Np63 TAp73 complexes and signatures genome wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing ChIP-seq TNF- enhanced genome-wide co-occupancy of cREL with Np63 on TP53 p63 sites while unexpectedly promoting redistribution of TAp73 from TP53 to activator protein-1 AP-1 sites cREL Np63 and TAp73 binding and oligomerization on NF- B- TP53- or AP-1-specific sequences were independently validated by ChIP-qPCR quantitative PCR oligonucleotide-binding assays and analytical ultracentrifugation Function of the binding activity was confirmed using TP53- AP-1- and NF- B-specific REs or p21 SERPINE1 and IL-6 promoter luciferase reporter activities Concurrently TNF- regulated a broad gene network with cobinding activities for cREL Np63 and TAp73 observed upon array profiling and reverse transcription PCR Overlapping target gene signatures were observed in squamous cancer subsets and in inflamed skin of transgenic mice overexpressing Np63 Furthermore multiple target genes identified in this study were linked to TP63 and TP73 activity and increased gene expression in large squamous cancer samples from PanCancer 12 TCGA by CircleMap PARADIGM inferred pathway analysis revealed the network connection of TP63 and NF- B complexes through an AP-1 hub further supporting our findings Thus inflammatory cytokine TNF- mediates genome-wide redistribution of the cREL p63 p73 and AP-1 interactome to diminish TAp73 tumor suppressor function and reciprocally activate NF- B and AP-1 gene programs implicated in malignancy

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TNF-α modulates genome-wide redistribution of ΔNp63α/TAp73 and NF-κB cREL interactive binding on TP53 and AP-1 motifs to...