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| Status |
Public on Feb 20, 2025 |
| Title |
Inhibition of SP/KLF transcription regulatory network and histone deacetylases acts synergistically against H3K27M-DIPG |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Diffuse intrinsic pontine gliomas (DIPGs), frequently harboring H3K27M mutations, are lethal pediatric brain tumors within no effective treatment. Here our epigenomic analyses uncover a marked enrichment of the SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. We show that SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized Mithramycin analog, significantly suppresses the proliferation and invasiveness of H3K27M-DIPG cells. In a screen of epigenetic drugs, we find that histone deacetylase inhibitors (HDACi) synergize with EC-8042 to suppress H3K27M-DIPG cell growth. The RNA-seq in SU-DIPG-IV and SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042 revealed that HDACi activates transcriptional programs that enhance tumor adaptability and invasiveness, an effect counteracted by EC-8042. And EC-8042 in combination with HDACi synergistically represses the expression of cell cycle-associated genes and therefore suppresses H3K27M-DIPG cell proliferation, inhibiting tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients. Therefore, our regulome profiling in H3K27M-DIPGs has provided mechanistic insights into HDACi resistance and a proof-of-concept for novel targeting therapeutics.
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| Overall design |
RNA-seq in SU-DIPG-IV and SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042.
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| Contributor(s) |
Kong Y, Lv X, Zhao Y, Dai Z, Zhao Q, Wang F |
| Citation missing |
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| Submission date |
Feb 04, 2024 |
| Last update date |
Feb 20, 2025 |
| Contact name |
Yu Kong |
| E-mail(s) |
kongyu@tmu.edu.cn
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| Phone |
15022088349
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| Organization name |
Tianjin Medical University
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| Street address |
22nd Qixiangtai Road
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| City |
Tianjin |
| ZIP/Postal code |
300070 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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