INSM2 promotes the development of neuroblastoma by regulating lipid metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201173 | GEO | 2022/07/04
REPOSITORIES: GEO
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Project description:INSM2 promotes the development of neuroblastoma by regulating lipid metabolism
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Project description:Studies have shown that PHOX2B is the first predisposition gene identified in neuroblastoma.To explore PHOX2B-dependent gene regulation, RNA-seq analysis was performed. Compared with the control group, PHOX2B knockdown SK-N-BE(2) cells showed differently expressed genes. We found that PHOX2B activates the MAPK signaling pathway to promote the occurrence and development of neuroblastoma.
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Project description:We report a previously unrecognized role of SAPCD2 in E2F signaling pathway in neuroblastoma. To explore SAPCD2-dependent gene regulation, RNA-seq analysis was conducted and the differently expressed genes were revealed in the SAPCD2-knockdown SK-N-BE(2) cells in comparison to control group. We find that SAPCD2 contributes to E2F7 mislocalization and decreases the level of nuclear E2F7 in NB cells, thus restraining the inhibitory effect of nuclear E2F7 on E2F signaling pathway. SAPCD2 knockdown limits the overactivation of E2F signaling in NB cells, affects the expression of genes involved in cell cycle and chromosome stability, and thereby blocking tumor progression.
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Project description:We report a previously unrecognized role of IGF2BP3 in survival of neuroblastoma cells. To explore IGF2BP3-dependent gene regulation and m6A modification, RNA-seq and m6A-seq analysis was conducted and the differently expressed/modified genes were revealed in the IGF2BP3-knockdown SK-N-BE(2) cells in comparison to control group.
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Project description:Neuroblastoma is the most common heterogeneous solid tumor in childhood, with limited treatments available for high-risk patients. Previous studies have shown that Dihydroorotate dehydrogenase (DHODH) plays an essential role in the de novo synthesis of pyrimidine and have identified it as a potential therapeutic target in cancer. Our previous studies have shown that the higher expression of DHODH is associated with the worst survival of neuroblastoma patients. Through knockdown experiments, we validated that reducing DHODH expression in neuroblastoma cells leads to a decrease in cell viability. Subsequently, we harnessed virtual screening software to repurpose drugs, targeting DHODH as potential neuroblastoma therapeutics. We conducted molecular docking simulations with a database of 2702 FDA-approved drugs on DHODH and identified a number of drugs that demonstrated high affinity for DHODH. Among these drugs, we found Regorafenib, a multi-kinase inhibitor, effectively inhibited neuroblastoma cell proliferation and was more efficient than leflunomide, an FDA-approved DHODH inhibitor. To determine whether Regorafenib is a novel DHODH inhibitor, we employed thermal shift and enzyme fluorescence assays. These assays revealed that Regorafenib not only enhanced binding stability but also reduced the enzymatic activity of DHODH. Since Regorafenib is a multi-kinase inhibitor, we confirm changes in downstream proteins by comparison with shDHODH to determine whether these alterations result from targeting DHODH. To further investigate the molecular mechanism of Regorafenib in targeting DHODH, we conducted a proteome analysis using tandem mass tag (TMT) labeling. This involved comparing samples treated with Regorafenib to those with DHODH knockdown. Using Liquid Chromatograph-mass spectrometry/ mass spectrometry (LC-MS/MS), a total of 4471 proteins and 31518 peptides were identified. Furthermore, we identified 377 differentially expressed proteins in the shDHODH sample and 225 in the Regorafenib treatment sample. We performed gene ontology (GO) enrichment analysis on these two sets of samples. The results of the GO enrichment analysis indicate that these proteins are associated with lipid metabolism in terms of biological functions. Through literature searches, we found that the results from proteomics analysis and Western blot validation both show that the commonly differentially expressed proteins are related to the mevalonate pathway. This pathway, when affected, influences ferroptosis. Additionally, we discovered a relationship between DHODH inhibition and lipid droplet production. In summary, previous studies have shown a connection between DHODH and ferroptosis. However, we identified a new mechanism where DHODH inhibition induces ferroptosis by affecting the mevalonate pathway. Therefore, our findings underscore the potential of using Regorafenib to target DHODH, proposing a novel and promising therapeutic strategy for high-risk neuroblastoma.
2025-08-07 | PXD054654 | JPOST Repository
Project description:Neuroblastoma is the most common heterogeneous solid tumor in childhood, with limited treatments available for high-risk patients. Previous studies have shown that Dihydroorotate dehydrogenase (DHODH) plays an essential role in the de novo synthesis of pyrimidine and have identified it as a potential therapeutic target in cancer. Our previous studies have shown that the higher expression of DHODH is associated with the worst survival of neuroblastoma patients. Through knockdown experiments, we validated that reducing DHODH expression in neuroblastoma cells leads to a decrease in cell viability. Subsequently, we harnessed virtual screening software to repurpose drugs, targeting DHODH as potential neuroblastoma therapeutics. We conducted molecular docking simulations with a database of 2702 FDA-approved drugs on DHODH and identified a number of drugs that demonstrated high affinity for DHODH. Among these drugs, we found regorafenib, a multi-kinase inhibitor, effectively inhibited neuroblastoma cell proliferation and was more efficient than leflunomide, an FDA-approved DHODH inhibitor. To determine whether regorafenib is a novel DHODH inhibitor, we employed thermal shift and enzyme fluorescence assays. These assays revealed that regorafenib not only enhanced binding stability but also reduced the enzymatic activity of DHODH. Since regorafenib is a multi-kinase inhibitor, we confirm changes in downstream proteins by comparison with shDHODH to determine whether these alterations result from targeting DHODH. To further investigate the molecular mechanism of regorafenib in targeting DHODH, we conducted a proteome analysis using tandem mass tag (TMT) labeling. This involved comparing samples treated with regorafenib to those with DHODH knockdown. Using Liquid Chromatograph-mass spectrometry/ mass spectrometry (LC-MS/MS), a total of 4471 proteins and 31518 peptides were identified. Furthermore, we identified 343 differentially expressed proteins in the shDHODH sample and 225 in the regorafenib treatment sample. We performed gene ontology (GO) enrichment analysis on these two sets of samples. The results of the GO enrichment analysis, focusing on biological function, indicated that proteins were correlated with lipid metabolism. After a research search, the proteome data and validation through western blot revealed common differentially expressed proteins related to the mevalonate pathway and subsequently linked to ferroptosis. Additionally, previous studies suggest a connection between DHODH and ferroptosis, leading us to investigate whether regorafenib treatment influences ferroptosis as confirmation that our drug targets DHODH. Moreover, neuroblastoma cells could be rescued by ferroptosis inhibitor liproxstatin-1. In summary, our findings highlight the potential of using regorafenib to target DHODH, presenting a promising therapeutic strategy for high-risk neuroblastoma.
2025-08-07 | PXD052506 | JPOST Repository
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