NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma [CUT&TAG]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1204986 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31864134_1.fastq.gz | Fastqsanger.gz | |||
| SRR31864134_2.fastq.gz | Fastqsanger.gz | |||
| SRR31864135_1.fastq.gz | Fastqsanger.gz | |||
| SRR31864135_2.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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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.
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Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma
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