TY - JOUR
T1 - Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling
AU - Rahnamoun, Homa
AU - Lu, Hanbin
AU - Duttke, Sascha H.
AU - Benner, Christopher
AU - Glass, Christopher K.
AU - Lauberth, Shannon M.
N1 - Funding Information:
We are grateful to Trenton Massey and Zhengxi Sun for technical assistance; Graham McVicker (Salk Institute) for insightful discussions of the project; Xinbin Chen (UC Davis) for providing the SW480 shLacZ and shp53 cell lines, and Gourisankar Ghosh (UC San Diego) for providing purified p65 protein. This work was supported by the Research Scholar Award from the Sidney Kimmel Foundation for Cancer Research #857A6A to S.M.L. and CRI-Irvington Fellowship to S.H.D.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-01117-y
DO - 10.1038/s41467-017-01117-y
M3 - Article
C2 - 28963538
AN - SCOPUS:85030318071
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 754
ER -
