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| Status |
Public on Feb 26, 2020 |
| Title |
Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Mutations in the DNA binding domain (DBD) of TP53 are often associated with the gain-of-function (GOF) of mutp53, resulting in pervasive transcription of chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Efforts to target this tumor-promoting function of mutp53 remain elusive. Here, we therapeutically exploit the GOF mechanisms of p53 codon 158 mutation, a DBD mutant found to be prevalent in lung squamous cell carcinoma. Using high throughput compound screening and combination analyses, we uncovered that mutp53R158G exhibits strong synergistic cytotoxicity to cisplatin-induced DNA stress and belinostat, a histone deacetylase inhibitor. This treatment regime acetylates mutp53, alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signalling and inducing apoptosis. This mechanistic intervention was validated with other acetylators of mutp53 and in several cancer models. Given that this transcriptional modulation and cytotoxic vulnerability appears inapt in p53 wild-type (WT) or null cells, our work provides a novel therapeutic opportunity in Arg158 15 -mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically.
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| |
|
| Overall design |
ChIP samples of TP53 wild type and mutant, treated and untreated from a cell line were analyzed by next-generation sequencing (Illumina HiSeq 2000).
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| |
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| Contributor(s) |
Kong LR, Tan TZ |
| Citation(s) |
32350249 |
| |
| Submission date |
Mar 21, 2019 |
| Last update date |
May 12, 2020 |
| Contact name |
Tuan Zea Tan |
| E-mail(s) |
csittz@nus.edu.sg
|
| Organization name |
National University of Singapore
|
| Department |
Cancer Science Institute Singapore
|
| Street address |
14 Medical Drive, #11-01, Singapore
|
| City |
Singapore |
| ZIP/Postal code |
117599 |
| Country |
Singapore |
| |
|
| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE129027 |
Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation |
|
| Relations |
| BioProject |
PRJNA528475 |
| SRA |
SRP189086 |
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