Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Abstract Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is signif...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-10-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42025-8 |
| _version_ | 1797558519214374912 |
|---|---|
| author | Lianhui Sun Yuan Zhang Boyu Yang Sijun Sun Pengshan Zhang Zai Luo Tingting Feng Zelin Cui Ting Zhu Yuming Li Zhengjun Qiu Guangjian Fan Chen Huang |
| author_facet | Lianhui Sun Yuan Zhang Boyu Yang Sijun Sun Pengshan Zhang Zai Luo Tingting Feng Zelin Cui Ting Zhu Yuming Li Zhengjun Qiu Guangjian Fan Chen Huang |
| author_sort | Lianhui Sun |
| collection | DOAJ |
| description | Abstract Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC. |
| first_indexed | 2024-03-10T17:31:34Z |
| format | Article |
| id | doaj.art-5db9a4a545be44c3b1fa6184874118e4 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:34Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5db9a4a545be44c3b1fa6184874118e42023-11-20T09:59:06ZengNature PortfolioNature Communications2041-17232023-10-0114111610.1038/s41467-023-42025-8Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancerLianhui Sun0Yuan Zhang1Boyu Yang2Sijun Sun3Pengshan Zhang4Zai Luo5Tingting Feng6Zelin Cui7Ting Zhu8Yuming Li9Zhengjun Qiu10Guangjian Fan11Chen Huang12Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicinePrecision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicinePrecision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineAbstract Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.https://doi.org/10.1038/s41467-023-42025-8 |
| spellingShingle | Lianhui Sun Yuan Zhang Boyu Yang Sijun Sun Pengshan Zhang Zai Luo Tingting Feng Zelin Cui Ting Zhu Yuming Li Zhengjun Qiu Guangjian Fan Chen Huang Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer Nature Communications |
| title | Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer |
| title_full | Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer |
| title_fullStr | Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer |
| title_full_unstemmed | Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer |
| title_short | Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer |
| title_sort | lactylation of mettl16 promotes cuproptosis via m6a modification on fdx1 mrna in gastric cancer |
| url | https://doi.org/10.1038/s41467-023-42025-8 |
| work_keys_str_mv | AT lianhuisun lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT yuanzhang lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT boyuyang lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT sijunsun lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT pengshanzhang lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT zailuo lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT tingtingfeng lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT zelincui lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT tingzhu lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT yumingli lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT zhengjunqiu lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT guangjianfan lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer AT chenhuang lactylationofmettl16promotescuproptosisviam6amodificationonfdx1mrnaingastriccancer |