The Cancer Genome Atlas (TCGA) netw

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 co-modulated by cREL/
ΔNp63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas
(HNSCC). However, how inflammatory gene signatures and cREL/p63/p73 targets are co-
modulated genome-wide is unclear. Here, we examined how inflammatory factor 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, oligonucleotide-binding assays, and
analytical ultracentrifugation. Function of the binding activity was confirmed using TP53, AP-1,
and NF-κB specific response elements, or p21, SERPINE1 , and IL-6 promoter luciferase reporter
activities. Concurrently, TNF-α regulated a broad gene network with co-binding activities for
cREL, ΔNp63α, and TAp73 observed upon array profiling and RT-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.

結果 (英文) 2:

At The. Cancer the Genome the Atlas (TCGA) Network Study of 12 Cancer types (PanCancer 12) Revealed
Frequent mutation of the TP53, and Amplification and expression The of Related TP63 isoform [Delta] Np63 in
squamous cancers. Australia Further, aberrant expression The of inflammatory Genes and the TP53 / of p63 / of p73 Targets
were Detected in at The PanCancer 12 Project, reminiscent of Gene Programs CO-modulated by CREL /
[Delta] Np63 / TAp73 Transcription Factors We Uncovered in head and Neck squamous the Cell carcinomas
(HNSCC). HOWEVER, How inflammatory Gene Signatures and CREL / of p63 / of p73 Targets are CO-
modulated the Genome-Wide IS Unclear. Here, We Examined How-inflammatory Factor of TNF [alpha] Broadly
modulates redistribution of the with ΔNp63α CREL / TAp73 Complexes and Signatures in the Genome-Wide
at The Model HNSCC the UM-SCC46 a using chromatin immunoprecipitation Sequencing (ChIP-SEQ) .
of TNF-[alpha] Enhanced the Genome-Wide CO-occupancy of CREL the with ΔNp63α ON the TP53 / of p63 sites, the while
unexpectedly Promoting redistribution of TAp73 from the TP53 to the Activator Protein-1 (the AP-1) sites.
CREL, ΔNp63α, and TAp73 Binding and oligomerization ON of NF-kappa] B, the TP53 or the AP-1 specific
Sequences & were Independently the Validated by the ChIP-the qPCR, Oligonucleotide-Binding the Assays, and
Analytical ultracentrifugation. the Function of at The Binding Activity WAS Con- firmed a using the TP53, the AP-1,
and of NF-kappa] B specific Response Elements , or of p21, SERPINE1, and of IL-. 6 promoter luciferase Reporter
Activities. CONCURRENTLY, of TNF-[alpha] regulated A Broad Gene Network the with CO-Binding Activities for
CREL, ΔNp63α, and TAp73 with the observed upon Array Profiling and RT-the PCR. Overlapping target The Gene
Signatures It was with the observed in squamous Cancer Subsets and in inflamed Skin of transgenic MICE
overexpressing ΔNp63α. furthermore, Multiple target The Genes IDENTIFIED in the this Study were linked to
TP63 and TP73 Activity and Increased Gene expression The in Large squamous Cancer the Samples from
PanCancer 12 TCGA by CircleMap. PARADIGM inferred pathway the Analysis Revealed at The Network
Connection of TP63 and of NF-[kappa] B Complexes through AN the AP-1 Hub, Australia Further Supporting Our Findings.
THUS, inflammatory cytokine of TNF-[alpha] mediates the Genome-Wide redistribution of at The CREL / of p63 / of p73,
and the AP-1 interactome , to Diminish TAp73 tumor Suppressor function and reciprocally of an activate NF-
[kappa] B and the AP-1 Gene Programs implicated in malignancy.