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.
| Original language | English (US) |
|---|---|
| Article number | 754 |
| Journal | Nature communications |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2017 |
Funding
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.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
