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TNF-α modulates genome-wide redistribution of ΔNp63α/TAp73 and NF-κB cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer.
- Source :
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Oncogene [Oncogene] 2016 Nov 03; Vol. 35 (44), pp. 5781-5794. Date of Electronic Publication: 2016 May 02. - Publication Year :
- 2016
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Abstract
- The Cancer Genome Atlas (TCGA) network study of 12 cancer types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ΔNp63 in squamous cancers. Further, aberrant expression of inflammatory genes and TP53/p63/p73 targets were detected in the PanCancer 12 project, reminiscent of gene programs comodulated by cREL/ΔNp63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas (HNSCCs). However, how inflammatory gene signatures and cREL/p63/p73 targets are comodulated genome wide is unclear. Here, we examined how the inflammatory factor tumor necrosis factor-α (TNF-α) broadly modulates redistribution of cREL with ΔNp63α/TAp73 complexes and signatures genome wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-α enhanced genome-wide co-occupancy of cREL with ΔNp63α on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to activator protein-1 (AP-1) sites. cREL, ΔNp63α and TAp73 binding and oligomerization on NF-κB-, TP53- or AP-1-specific sequences were independently validated by ChIP-qPCR (quantitative PCR), oligonucleotide-binding assays and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53-, AP-1- and NF-κB-specific REs or p21, SERPINE1 and IL-6 promoter luciferase reporter activities. Concurrently, TNF-α regulated a broad gene network with cobinding activities for cREL, ΔNp63α and TAp73 observed upon array profiling and reverse transcription-PCR. Overlapping target gene signatures were observed in squamous cancer subsets and in inflamed skin of transgenic mice overexpressing ΔNp63α. Furthermore, multiple target genes identified in this study were linked to TP63 and TP73 activity and increased gene expression in large squamous cancer samples from PanCancer 12 TCGA by CircleMap. PARADIGM inferred pathway analysis revealed the network connection of TP63 and NF-κB complexes through an AP-1 hub, further supporting our findings. Thus, inflammatory cytokine TNF-α mediates genome-wide redistribution of the cREL/p63/p73, and AP-1 interactome, to diminish TAp73 tumor suppressor function and reciprocally activate NF-κB and AP-1 gene programs implicated in malignancy.
- Subjects :
- Binding Sites
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
Cluster Analysis
Consensus Sequence
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Models, Biological
Nucleotide Motifs
Promoter Regions, Genetic
Protein Binding
Protein Transport
Regulatory Sequences, Nucleic Acid
Response Elements
Signal Transduction
Transcription Factors genetics
Transcription Initiation Site
Transcriptional Activation
Tumor Protein p73 genetics
Tumor Suppressor Proteins genetics
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell metabolism
NF-kappa B metabolism
Transcription Factor AP-1 metabolism
Transcription Factors metabolism
Tumor Necrosis Factor-alpha metabolism
Tumor Protein p73 metabolism
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 35
- Issue :
- 44
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 27132513
- Full Text :
- https://doi.org/10.1038/onc.2016.112