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

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

Author information

1
Section of Molecular Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0651, USA.
3
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0651, USA.
4
Section of Molecular Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. slauberth@ucsd.edu.

Abstract

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.

PMID:
28963538
PMCID:
PMC5622043
DOI:
10.1038/s41467-017-01117-y
[Indexed for MEDLINE]
Free PMC Article

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