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

Nat Commun. 2017 Sep 29;8(1):754. doi: 10.1038/s41467-017-01117-y.


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 NFκB that drives alterations in enhancer and gene activation in response to chronic TNF-α signaling. We show that p53 mutants interact directly with NFκB 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-α signaling orchestrates a functional interplay between mutant p53 and NFκB that underlies altered patterns of cancer-promoting gene expression.Inflammation is known to affect cancer development, yet the mechanisms by which immune signaling drives transformation remain unclear. Here, the authors provide evidence that chronic TNF-α signaling promotes the enhancer binding and transcriptional interplay between mutant p53 and NFκB.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Enhancer Elements, Genetic*
  • Humans
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Protein Binding
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / immunology


  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53