Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer

Lianhui Sun, Yuan Zhang, Boyu Yang, Sijun Sun, Pengshan Zhang, Zai Luo, Tingting Feng, Zelin Cui, Ting Zhu, Yuming Li, Zhengjun Qiu, Guangjian Fan () and Chen Huang ()
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Lianhui Sun: Shanghai Jiao Tong University School of Medicine
Yuan Zhang: Shanghai Jiao Tong University School of Medicine
Boyu Yang: Capital Medical University
Sijun Sun: Shanghai Jiao Tong University School of Medicine
Pengshan Zhang: Shanghai Jiao Tong University School of Medicine
Zai Luo: Shanghai Jiao Tong University School of Medicine
Tingting Feng: Shanghai Jiao Tong University School of Medicine
Zelin Cui: Shanghai Jiao Tong University School of Medicine
Ting Zhu: Shanghai Jiao Tong University School of Medicine
Yuming Li: Shanghai Jiao Tong University School of Medicine
Zhengjun Qiu: Shanghai Jiao Tong University School of Medicine
Guangjian Fan: Shanghai Jiao Tong University School of Medicine
Chen Huang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42025-8

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