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| Status |
Public on Sep 17, 2018 |
| Title |
Super-enhancer-driven CCAT1 is co-activated by SOX2 and TP63 and promotes squamous cancer from esophagus, head and neck and lung [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that the transcription factors TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. Our recent study have identified TP63 and SOX2 as super-enhancer-associated genes. However, functional consequences of their frequent co-localization at super-enhancers region remains unexplored. Here, ChIP-seq result indicated TP63 and SOX2 co-occupied peaks are significantly located the super enhancer region compare with unique of TP63 and SOX2 signaling, and combined RNA-seq analyses of different types of SCCs reveal that TP63 and SOX2 cooperatively regulate expression of the super-enhancer-associated the long non-coding RNA (lncRNA) gene, CCAT1. CCAT1 is highly expressed in SCCs compared to either other tumor types or normal tissues. CCAT1 expression strongly correlates with expression levels of TP63 and SOX2. Silencing of CCAT1 significantly reduces cellular growth both in vitro and in vivo, phenotyping the effect of silencing either TP63 or SOX2. Furthermore, ChIP-Seq and luciferase reporter assays demonstrate TP63 and SOX2 co-occupy the promoter and super-enhancer regions of CCAT1. Interaction of CCAT1 with TP63 and SOX2 are validated by RNA immunoprecipitation. In addition, ChIRP analysis suggests that CCAT1 regulates EGFR expression by binding to the super-enhancer of EGFR. Further investigations shows that CCAT1 activates both the MEK/ERK1/2 and PI3K/AKT signaling pathways through up-regulation of EGFR. In conclusion, CCAT1 is driven by master transcription factors TP63 and SOX2 and is recruited to the super-enhancer of EGFR, promoting SCC tumorigenesis through activation of the MEK/ERK1/2 and PI3K/AKT signaling pathways. These studies help to explain the pathogenesis of SCC and aids in providing novel therapeutic strategy.
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| Overall design |
ChIP sequencing of H3K27Ac histone modifications, TP63, and SOX2 binding occupancies in Esophageal Squamous Cell Carcinoma cell lines
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| Contributor(s) |
Jiang Y, Lin D, Koeffler PH, Jiang Y |
| Citation(s) |
30190462 |
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| Submission date |
Nov 06, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Phillip H Koeffler |
| E-mail(s) |
phillip_koeffler@nuhs.edu.sg
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| Organization name |
Cancer Science Institute
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| Lab |
H. Phillip Koeffler's lab
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| Street address |
14 Medical Drive
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| City |
Singapore |
| ZIP/Postal code |
117599 |
| Country |
Singapore |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE106565 |
Super-enhancer-driven CCAT1 is co-activated by SOX2 and TP63 and promotes squamous cancer from esophagus, head and neck and lung |
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| Relations |
| BioProject |
PRJNA417252 |
| SRA |
SRP124242 |