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.
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.
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作者：
12种癌症类型的癌症基因组图谱（TCGA）网络研究（PanCancer 12）揭示了鳞状细胞癌中TP 53的频繁突变以及相关TP 63亚型Δ Np 63的扩增和表达。此外，在PanCancer 12项目中检测到炎性基因和TP 53/p63/p73靶点的异常表达，这让人想起我们在头颈部鳞状细胞癌（HNSCC）中发现的cREL/Δ Np 63/TAp 73转录因子共调控的基因程序。然而，炎症基因签名和cREL/p63/p73靶标如何在全基因组范围内共同调节尚不清楚。在这里，我们使用染色质免疫沉淀测序（ChIP-seq）研究了炎症因子TNF-α如何在HNSCC模型UM-SCC 46中广泛调节cREL与Δ Np 63 α/TAp 73复合物和全基因组特征的再分布。TNF-α增强了cREL与Δ Np 63 α在TP 53/p63位点的全基因组共占据，同时意外地促进了TAp 73从TP 53重新分布到激活蛋白-1（AP-1）位点。通过ChIP-qPCR、阿托伐他汀结合试验和分析性超离心，独立验证了NF-κB、TP 53或AP-1特异性序列上的cREL、Δ Np 63 α和TAp 73结合和寡聚化。使用TP 53、AP-1和NF-κB特异性反应元件或p21、SERPINE 1和IL-6启动子荧光素酶报告基因活性确认结合活性的功能。同时，TNF-α调节广泛的基因网络，在阵列分析和RT-PCR中观察到cREL、Δ Np 63 α和TAp 73的共结合活性。在鳞状细胞癌亚群和过度表达Δ Np 63 α的转基因小鼠的炎症皮肤中观察到重叠的靶基因特征。此外，通过CircleMap，本研究中鉴定的多个靶基因与来自PanCancer 12 TCGA的大型鳞状细胞癌样品中的TP 63和TP 73活性和增加的基因表达相关。PARADIGM推测的通路分析揭示了TP 63和NF-κB复合物通过AP-1枢纽的网络连接，进一步支持了我们的发现。因此，炎性细胞因子TNF-α介导cREL/p63/p73和AP-1相互作用组的全基因组重新分布，以减少TAp 73肿瘤抑制功能并重新激活与恶性肿瘤有关的NF-κB和AP-1基因程序。
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.
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影响因子：
11.2
作者：
King KE;Ponnamperuma RM;Allen C;Lu H;Duggal P;Chen Z;Van Waes C;Weinberg WC
通讯作者：
Weinberg WC
影响因子：
11.2
作者：
Chatterjee A;Chang X;Sen T;Ravi R;Bedi A;Sidransky D
通讯作者：
Sidransky D
影响因子：
64.8
作者：
Boccaccio, C;Sabatino, G;Comoglio, PM
通讯作者：
Comoglio, PM
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
7.3
作者：
Koshiba, S.;Ichimiya, S.;Sato, N.
通讯作者：
Sato, N.