NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma [CUT&TAG]
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ABSTRACT:
PROVIDER: PRJNA1204986 | ENA |
REPOSITORIES: ENA
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Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285628 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285627 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285630 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285629 | GEO
Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma
| PRJNA1204984 | ENA
Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma [ChiP-seq]
| PRJNA1204987 | ENA
Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma [ATAC-seq]
| PRJNA1204989 | ENA
Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma [RNA-seq]
| PRJNA1204988 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-05-01 | GSE285631 | GEO
Project description:HAND2, MEIS2 and TCF4 are master transcription factors (TFs) in neuroblastoma and create an interconnected core regulatory circuitry (CRC) by directly occupying each other's and their own super-enhancers (SEs), which leads to high levels of each TF expression inside the CRC. Additionally, CRC TFs cooperatively co-occupy the same SE components, which promotes the expression of genes involved in cell identity and cell-type-specific activities. Super-enhancer-mediated CRC enriched at key oncogenes in neuroblastoma. In the present study, CUT&Tag (Cleavage Under Targets and Tagmentation) analysis was performed to explore the target of HAND2, MEIS2 and TCF4 in NB cells.
2024-05-06 | GSE234337 | GEO