DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior
Abstract Background Variations in DNA methylation within the DNA damage response (DDR) mechanism could have significant implications for glioma prognosis and immune responses. This study aimed to explore the global DNA methylation landscape of DDR genes in gliomas and identify key epigenetically reg...
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BMC
2025-08-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06360-2 |
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| author | An-an Yin Yan Yao Yi-feng Liu Yu-sha Ji Ya-long He Tian-chi Ma Wen-heng Guo Amandine Etcheverry Marc Aubry Jean Mosser Wei Lin Yuan-ming Wu Kun Chen |
| author_facet | An-an Yin Yan Yao Yi-feng Liu Yu-sha Ji Ya-long He Tian-chi Ma Wen-heng Guo Amandine Etcheverry Marc Aubry Jean Mosser Wei Lin Yuan-ming Wu Kun Chen |
| author_sort | An-an Yin |
| collection | DOAJ |
| description | Abstract Background Variations in DNA methylation within the DNA damage response (DDR) mechanism could have significant implications for glioma prognosis and immune responses. This study aimed to explore the global DNA methylation landscape of DDR genes in gliomas and identify key epigenetically regulated genes influencing glioma biology and immunity. Methods This study incorporated a range of public and local glioma datasets. Multiple clinical, bioinformatic, and in vitro experimental analyses were conducted to explore clinical and biological aspects. Results Global DNA methylation variations in DDR genes correlated with distinct glioma prognoses, with five CpGs identified as potent predictors. Hierarchical clustering and a risk-score model based on these CpGs unveiled immune-related prognostic subgroups in glioblastomas (GBMs) and lower-grade gliomas (LGGs). NSUN5, epigenetically regulated by one of these CpGs, highlighted the biological significance of the DDR CpG panel. In vitro, NSUN5 displayed tumor-suppressor-like activities in GBM cells, but clinically, it was an unfavorable prognostic marker. Depletion of NSUN5 shifted cytosolic DNA sensing from a STING-dependent (cGAS-STING) pathway to a STING-independent (DNA-PK-HSPA8) pathway, leading to a delayed but more robust type I interferon (IFN) response in GBM cells and enhancing microglial M1 polarization and chemotaxis. This may partially account for the functional discrepancy of NSUN5 observed between experimental and clinical contexts. Conclusion This study highlights the complex interplay between DNA methylation, the DDR mechanism, cytosolic DNA sensing, and glioma immunity. These findings may inspire novel strategies for DNA sensing-based immunotherapy. |
| format | Article |
| id | doaj-art-1fe49542a6e24ae0b7dc22d31e8f6cd9 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-1fe49542a6e24ae0b7dc22d31e8f6cd92025-08-20T04:03:07ZengBMCJournal of Translational Medicine1479-58762025-08-0123111610.1186/s12967-025-06360-2DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behaviorAn-an Yin0Yan Yao1Yi-feng Liu2Yu-sha Ji3Ya-long He4Tian-chi Ma5Wen-heng Guo6Amandine Etcheverry7Marc Aubry8Jean Mosser9Wei Lin10Yuan-ming Wu11Kun Chen12Department of Plastic and Reconstructive Surgery, Xijing Hospital, Air Force Medical UniversityShaanxi Provincial Key Laboratory of Clinical Genetics, Air Force Medical UniversityShaanxi Provincial Key Laboratory of Clinical Genetics, Air Force Medical UniversityShaanxi Provincial Key Laboratory of Clinical Genetics, Air Force Medical UniversityDepartment of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Air Force Medical UniversityDepartment of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Air Force Medical UniversityDepartment of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Air Force Medical UniversityCNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR)CNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR)CNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR)Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Air Force Medical UniversityShaanxi Provincial Key Laboratory of Clinical Genetics, Air Force Medical UniversityDepartment of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, Air Force Medical UniversityAbstract Background Variations in DNA methylation within the DNA damage response (DDR) mechanism could have significant implications for glioma prognosis and immune responses. This study aimed to explore the global DNA methylation landscape of DDR genes in gliomas and identify key epigenetically regulated genes influencing glioma biology and immunity. Methods This study incorporated a range of public and local glioma datasets. Multiple clinical, bioinformatic, and in vitro experimental analyses were conducted to explore clinical and biological aspects. Results Global DNA methylation variations in DDR genes correlated with distinct glioma prognoses, with five CpGs identified as potent predictors. Hierarchical clustering and a risk-score model based on these CpGs unveiled immune-related prognostic subgroups in glioblastomas (GBMs) and lower-grade gliomas (LGGs). NSUN5, epigenetically regulated by one of these CpGs, highlighted the biological significance of the DDR CpG panel. In vitro, NSUN5 displayed tumor-suppressor-like activities in GBM cells, but clinically, it was an unfavorable prognostic marker. Depletion of NSUN5 shifted cytosolic DNA sensing from a STING-dependent (cGAS-STING) pathway to a STING-independent (DNA-PK-HSPA8) pathway, leading to a delayed but more robust type I interferon (IFN) response in GBM cells and enhancing microglial M1 polarization and chemotaxis. This may partially account for the functional discrepancy of NSUN5 observed between experimental and clinical contexts. Conclusion This study highlights the complex interplay between DNA methylation, the DDR mechanism, cytosolic DNA sensing, and glioma immunity. These findings may inspire novel strategies for DNA sensing-based immunotherapy.https://doi.org/10.1186/s12967-025-06360-2GliomaDNA damage responseDNA methylationCytosolic DNA sensingNSUN5 |
| spellingShingle | An-an Yin Yan Yao Yi-feng Liu Yu-sha Ji Ya-long He Tian-chi Ma Wen-heng Guo Amandine Etcheverry Marc Aubry Jean Mosser Wei Lin Yuan-ming Wu Kun Chen DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior Journal of Translational Medicine Glioma DNA damage response DNA methylation Cytosolic DNA sensing NSUN5 |
| title | DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior |
| title_full | DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior |
| title_fullStr | DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior |
| title_full_unstemmed | DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior |
| title_short | DNA methylation variations of DNA damage response in glioblastoma: NSUN5 modulates tumor-intrinsic cytosolic DNA-sensing and microglial behavior |
| title_sort | dna methylation variations of dna damage response in glioblastoma nsun5 modulates tumor intrinsic cytosolic dna sensing and microglial behavior |
| topic | Glioma DNA damage response DNA methylation Cytosolic DNA sensing NSUN5 |
| url | https://doi.org/10.1186/s12967-025-06360-2 |
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