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TNF-α modulates genome-wide redistribution of ΔNp63α/TAp73 and NF-κB c-REL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer
Ist Teil von
Oncogene, 2016-05, Vol.35 (44), p.5781-5794
Erscheinungsjahr
2016
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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.