A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma
The BRAFV600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAFV600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetyl...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-10-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625001022 |
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| author | Jiang Zhou Xinxin Chai Yi Zhu Zhi Huang Tingting Lin Zhen Hu Guangdi Chen Chi Luo Rutao Cui Jinghao Sheng |
| author_facet | Jiang Zhou Xinxin Chai Yi Zhu Zhi Huang Tingting Lin Zhen Hu Guangdi Chen Chi Luo Rutao Cui Jinghao Sheng |
| author_sort | Jiang Zhou |
| collection | DOAJ |
| description | The BRAFV600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAFV600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAFV600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAFV600E-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAFV600E inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAFV600E inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients. |
| format | Article |
| id | doaj-art-50aa3fce7cc245f591e52fc0479a4a3d |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-50aa3fce7cc245f591e52fc0479a4a3d2025-08-25T04:14:10ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-10-016810122310.1016/j.neo.2025.101223A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanomaJiang Zhou0Xinxin Chai1Yi Zhu2Zhi Huang3Tingting Lin4Zhen Hu5Guangdi Chen6Chi Luo7Rutao Cui8Jinghao Sheng9Institute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Skin Disease Research Institute, The 2nd Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310058, ChinaInstitute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaInstitute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, ChinaInstitute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaInstitute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaInstitute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaInstitute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaLiangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Corresponding authors.Skin Disease Research Institute, The 2nd Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Corresponding authors.Institute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Skin Disease Research Institute, The 2nd Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310058, China; Corresponding authors.The BRAFV600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAFV600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAFV600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAFV600E-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAFV600E inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAFV600E inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients.http://www.sciencedirect.com/science/article/pii/S1476558625001022MelanomaBRAFV600EH3K27KDM6AMitochondrial MetabolismPGC1α |
| spellingShingle | Jiang Zhou Xinxin Chai Yi Zhu Zhi Huang Tingting Lin Zhen Hu Guangdi Chen Chi Luo Rutao Cui Jinghao Sheng A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma Neoplasia: An International Journal for Oncology Research Melanoma BRAFV600E H3K27 KDM6A Mitochondrial Metabolism PGC1α |
| title | A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma |
| title_full | A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma |
| title_fullStr | A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma |
| title_full_unstemmed | A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma |
| title_short | A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma |
| title_sort | methyl to acetyl switch in h3k27 drives metabolic reprogramming and resistance to brafv600e inhibition in melanoma |
| topic | Melanoma BRAFV600E H3K27 KDM6A Mitochondrial Metabolism PGC1α |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625001022 |
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