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| Status |
Public on Jul 29, 2024 |
| Title |
BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
In colorectal cancer (CRC), WNT/β-catenin signaling is aberrantly activated mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress WNT/β-catenin signaling, are under pre-clinical and clinical trials, while their resistance mechanisms remain unclear. In this study, we established tankyrase inhibitor-resistant CRC cells, JC73-RK100, from APC-mutated patient-derived CRC cells. JC73-RK100 cells and several CRC cells were sensitive to tankyrase inhibitors at low concentrations but were resistant at high concentrations (i.e., bell-shaped dose response: BSDR). Mechanistically, tankyrase inhibitors at high concentrations promoted BRD3/4-dependent E2F target gene transcription and over-activated cell cycle progression in the BSDR cells. BET inhibitors canceled the bell-shaped dose response to tankyrase inhibitors. Taken together, these observations suggest that combination of tankyrase and BET inhibitors would be a useful therapeutic approach to overcome a subset of resistance to tankyrase inhibitors.
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| Overall design |
Examination of histone modification (H3K27ac) and chromatin associated proteins (BRD3, BRD4) using CUT&RUN in colorectal cancer PDC JC73, JC73-RK100 and JC21 cells treated with or without tankyrase inhibitor RK-582.
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| |
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| Contributor(s) |
Morino S, Mashima T, Seimiya H |
| Citation(s) |
38216082 |
| |
| Submission date |
Jul 31, 2023 |
| Last update date |
Jul 30, 2024 |
| Contact name |
Shun Morino |
| E-mail(s) |
[email protected]
|
| Organization name |
JFCR
|
| Street address |
3-8-31, Ariake, Koto-ku
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| City |
Tokyo |
| ZIP/Postal code |
135-8550 |
| Country |
Japan |
| |
|
| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (36)
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| This SubSeries is part of SuperSeries: |
| GSE239683 |
BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer |
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| Relations |
| BioProject |
PRJNA1000550 |
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