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| Status |
Public on Mar 01, 2019 |
| Title |
Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid cancer [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancy and accounts for the majority of thyroid cancer-related deaths. Despite intensive research, there remains no effective treatment for patients with ATC. Here, we identify THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid cancer (PTC) cells, are exceptionally sensitive to CDK7 inhibition. Analyzing both gene expression profiles and super enhancer (SE) features reveals that the SE-mediated oncogenic transcriptional amplification renders the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays discovers a number of novel cancer genes of ATC, including PPP1R15A, SMG9 and KLF2. Inhibition of PPP1R15A with Guanabenz (GBZ) or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, GBZ or THZ1 treatment sensitizes ATC cells to conventional chemotherapy. Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.
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| Overall design |
ChIP-sequencing using H3K27ac antibody in BCPAP and CAL-62 cell lines.
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| Contributor(s) |
Chen Y, Cao X |
| Citation(s) |
30924726 |
| Submission date |
Sep 19, 2018 |
| Last update date |
Nov 07, 2019 |
| Contact name |
Xinyi Cao |
| E-mail(s) |
cxyldd@tmu.edu.cn
|
| Phone |
86-22-83336728
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| Organization name |
Collaborative Innovation Center of Tianjin for Medical Epigenetics
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| Street address |
Tianjin Medical University No.22 Qixiangtai Road
|
| City |
Tianjin |
| State/province |
Tianjin |
| ZIP/Postal code |
300070 |
| Country |
China |
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| Platforms (1) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE120177 |
Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid cancer |
|
| Relations |
| BioProject |
PRJNA491865 |
| SRA |
SRP162126 |
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