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| Status |
Public on Sep 06, 2022 |
| Title |
Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma [ATAC-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.
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| |
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| Overall design |
Examination of chromatin accessibility, histone modification post QC6352 treatments, KDM4B shRNA knockdown and overexpression Pax3-FOXO1 in RH30 or LHCN.
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| |
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| Contributor(s) |
Jie F, Shivendra S, Hongjian J, Jun Y |
| Citation(s) |
35857643 |
| Submission date |
Aug 28, 2020 |
| Last update date |
Sep 07, 2022 |
| Contact name |
Hongjian Jin |
| E-mail(s) |
hongjian.jin@STJUDE.ORG
|
| Organization name |
St Jude Children's Research Hospital
|
| Department |
Center for Applied Bioinformatics
|
| Street address |
262 Danny Thomas Place
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38015 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (14)
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| This SubSeries is part of SuperSeries: |
| GSE157095 |
Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma |
|
| Relations |
| BioProject |
PRJNA660046 |
| SRA |
SRP279247 |
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