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

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 e...

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Published in:Nature communications 2023-10, Vol.14 (1), p.6523-6523, Article 6523
Main Authors: Sun, Lianhui, Zhang, Yuan, Yang, Boyu, Sun, Sijun, Zhang, Pengshan, Luo, Zai, Feng, Tingting, Cui, Zelin, Zhu, Ting, Li, Yuming, Qiu, Zhengjun, Fan, Guangjian, Huang, Chen
Format: Article
Language:English
Subjects:
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Cancer
Cancer therapies
Copper
Gastric cancer
Histones
Humanities and Social Sciences
Methyltransferase
mRNA
multidisciplinary
N6-methyladenosine
RNA modification
Science
Science (multidisciplinary)
Tumors
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Summary: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 m 6 A 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. Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-42025-8