Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer.
Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer.
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DOI：
10.1038/s41467-023-42025-8
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发表时间：
2023-10-20
影响因子：
16.6
通讯作者：
Huang, Chen
中科院分区：
文献类型：
--
作者：
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
由铜浓度过高引起的铜中毒被紧急开发为潜在的癌症治疗方法。然而，肿瘤中铜凋亡的启动、传播和最终执行的机制仍然未知。在这里，我们发现胃癌（GC）中铜含量显着升高，尤其是恶性肿瘤中。筛选表明 METTL16 是一种非典型甲基转移酶，通过 FDX1 mRNA 上的 m6A 修饰而成为铜凋亡的关键介质。此外，铜应激促进 METTL16 在 K229 位点乳酰化，随后发生铜凋亡。 METTL16 乳酰化过程受到 SIRT2 的抑制。 METTL16 乳酰化水平升高可显着提高铜离子载体——艾氯醇的治疗效果。将艾司洛莫与 SIRT2 特异性抑制剂 AGK2 相结合，可在体外和体内诱导胃肿瘤的铜凋亡。这些结果揭示了非组蛋白蛋白 METTL16 乳酰化对肿瘤铜凋亡的重要性。鉴于 GC 中铜和乳酸浓度较高，铜凋亡诱导成为 GC 的一种有前途的治疗策略。肿瘤中铜中毒的调节尚不清楚。在这里，作者发现铜促进 METTL16 乳酰化，通过稳定胃癌中的 FDX1 诱导铜凋亡。靶向乳酰-METTL16 和铜凋亡为癌症治疗提供了一种潜在可行的策略。
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. 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.
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