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.
Highlights
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
Enhancer activity is often correlated with an enrichment of the histone mark, histone H3 lysine 27 acetylation (H3K27ac)[16,17,18] and RNA polymerase II (RNAPII) recruitment that drives the production of bidirectional transcripts known as enhancer RNAs19–22
To investigate the mechanisms underlying the roles of mutp[53] in promoting chronic inflammation-induced tumorigenesis, we performed mRNA sequencing in human SW480 colon cancer cells expressing doxycycline-inducible short hairpin RNAs against mutp[53] before and following TNF-α treatment for 16 h
Summary
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. 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 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. In recent support of the p53 GOF paradigm is the finding that mutant p53 (mutp53) augments NFκB activation and results in chronic but not acute inflammation-induced tumor initiation in a mouse model of inflammatory bowel disease[5] Another seminal study revealed that mutp[53] prolongs NFκB activation by inhibiting apoptosis-stimulated kinase (ASK1)-JNK pathways in response to chronic tumor necrosis factor alpha (TNF-α) signaling[6]. Our findings uncover an enhancer transcription “signature” that is linked to alterations in tumorpromoting gene expression and enhanced cancer cell growth
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