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KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ATAC-seq]

GSE164450 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 8 samples Submitted 2024/03/04 Platform GPL24676
Summary
A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.
Published in
Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma
Abu-Zaid A, Fang J, Jin H et al. · Cell reports. Medicine 2024 · PMID 38508144 · doi:10.1016/j.xcrm.2024.101468
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Also filed as BioProject PRJNA690789 and SRA study SRP300906. Searching any of these in the dataset finder brings you back here.

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