Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma
Abstract Background Neuroblastoma (NB) is the most common solid tumor in children, characterized by high recurrence rates, drug resistance, and significant mortality. Methods In this study, we analyzed the proteomic profiles of NB tissue samples alongside other pathological categories, including gan...
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BMC
2025-02-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06298-5 |
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| author | Zan Liu Zitong Zhao Longlong Xie Zhenghui Xiao Ming Li Yong Li Ting Luo |
| author_facet | Zan Liu Zitong Zhao Longlong Xie Zhenghui Xiao Ming Li Yong Li Ting Luo |
| author_sort | Zan Liu |
| collection | DOAJ |
| description | Abstract Background Neuroblastoma (NB) is the most common solid tumor in children, characterized by high recurrence rates, drug resistance, and significant mortality. Methods In this study, we analyzed the proteomic profiles of NB tissue samples alongside other pathological categories, including ganglioneuroma (GN) and ganglioneuroblastoma (GNB). Using weighted gene co-expression network analysis (WGCNA), the core prognostic gene models associated with histopathology of NB were identified. Furthermore, by mapping our core prognostic gene models onto drug-perturbed transcriptome profiles from the L1000FWD and CMap databases, repurposing drug candidates were screened and validated for NB. Results Our proteomic analysis reveals that pathways associated with the cell cycle and DNA replication are significantly upregulated in NB, while oxidative phosphorylation, pyruvate metabolism, and the TCA cycle are notably downregulated compared to GNB and GN. By applying WGCNA, we identified a core prognostic gene model strongly associated with the unfavorable subtype and high MKI of NB and primarily related to chromatin binding and mRNA metabolic process. Protein–protein interaction network analysis identified 15 hub genes in this core prognostic module: SMARCA4, SMARCA5, SMARCC2, SMARCC1, PBRM1, BRD3, ARID1A, BRD2, ARID1B, KDM1A, TP53BP1, ALYREF, CBX1, SF3B1, and ADNP, which mainly related to chromatin remodeling. Notably, SMARCA4 and ALYREF are also high-risk genes of mortality and validated as potential prognostic biomarkers for NB. Through repurposing drugs screening, mocetinostat and clofarabine were validated as effective treatments in two NB cell lines. Conclusion Mocetinostat and clofarabine offer valuable insights for the development of novel targeted therapies in neuroblastoma. |
| format | Article |
| id | doaj-art-60d73f06a5614c1bb6af87aa3eae911d |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-60d73f06a5614c1bb6af87aa3eae911d2025-08-20T03:03:45ZengBMCJournal of Translational Medicine1479-58762025-02-0123111110.1186/s12967-025-06298-5Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastomaZan Liu0Zitong Zhao1Longlong Xie2Zhenghui Xiao3Ming Li4Yong Li5Ting Luo6Department of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan Children’s Hospital)Center of Reproductive Medicine, Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal and Child Health Care of Hunan Normal UniversityDepartment of Radiology, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan Children’s Hospital)Emergency Center of Hunan Children’s Hospital, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South UniversityDepartment of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan Children’s Hospital)Department of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan Children’s Hospital)Pediatrics Research Institute, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan Children’s Hospital)Abstract Background Neuroblastoma (NB) is the most common solid tumor in children, characterized by high recurrence rates, drug resistance, and significant mortality. Methods In this study, we analyzed the proteomic profiles of NB tissue samples alongside other pathological categories, including ganglioneuroma (GN) and ganglioneuroblastoma (GNB). Using weighted gene co-expression network analysis (WGCNA), the core prognostic gene models associated with histopathology of NB were identified. Furthermore, by mapping our core prognostic gene models onto drug-perturbed transcriptome profiles from the L1000FWD and CMap databases, repurposing drug candidates were screened and validated for NB. Results Our proteomic analysis reveals that pathways associated with the cell cycle and DNA replication are significantly upregulated in NB, while oxidative phosphorylation, pyruvate metabolism, and the TCA cycle are notably downregulated compared to GNB and GN. By applying WGCNA, we identified a core prognostic gene model strongly associated with the unfavorable subtype and high MKI of NB and primarily related to chromatin binding and mRNA metabolic process. Protein–protein interaction network analysis identified 15 hub genes in this core prognostic module: SMARCA4, SMARCA5, SMARCC2, SMARCC1, PBRM1, BRD3, ARID1A, BRD2, ARID1B, KDM1A, TP53BP1, ALYREF, CBX1, SF3B1, and ADNP, which mainly related to chromatin remodeling. Notably, SMARCA4 and ALYREF are also high-risk genes of mortality and validated as potential prognostic biomarkers for NB. Through repurposing drugs screening, mocetinostat and clofarabine were validated as effective treatments in two NB cell lines. Conclusion Mocetinostat and clofarabine offer valuable insights for the development of novel targeted therapies in neuroblastoma.https://doi.org/10.1186/s12967-025-06298-5NeuroblastomaProteomicsChromatin-remodelingSMARCA4 |
| spellingShingle | Zan Liu Zitong Zhao Longlong Xie Zhenghui Xiao Ming Li Yong Li Ting Luo Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma Journal of Translational Medicine Neuroblastoma Proteomics Chromatin-remodeling SMARCA4 |
| title | Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma |
| title_full | Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma |
| title_fullStr | Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma |
| title_full_unstemmed | Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma |
| title_short | Proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma |
| title_sort | proteomic analysis reveals chromatin remodeling as a potential therapeutical target in neuroblastoma |
| topic | Neuroblastoma Proteomics Chromatin-remodeling SMARCA4 |
| url | https://doi.org/10.1186/s12967-025-06298-5 |
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