Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling

Inflammation influences cancer development, progression, and the efficacy of cancer treatments, yet the mechanisms by which immune signaling drives alterations in the cancer cell transcriptome remain unclear. Using ChIP-seq, RNA-seq, and GRO-seq, here we demonstrate a global overlap in the binding of tumor-promoting p53 mutants and the master proinflammatory regulator NF kappa B that drives alterations in enhancer and gene activation in response to chronic TNF-alpha signaling. We show that p53 mutants interact directly with NF kappa B and that both factors impact the other's binding at diverse sets of active enhancers. In turn, the simultaneous and cooperative binding of these factors is required to regulate RNAPII recruitment, the synthesis of enhancer RNAs, and the activation of tumor-promoting genes. Collectively, these findings establish a mechanism by which chronic TNF-alpha signaling orchestrates a functional interplay between mutant p53 and NF kappa B that underlies altered patterns of cancer-promoting gene expression.