Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
Nat Commun. 2023 Oct 20;14(1):6523. doi: 10.1038/s41467-023-42025-8.
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 mA 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.
铜死亡是由铜浓度过高引起的，目前正被紧急开发为一种潜在的癌症治疗方法。然而，肿瘤中铜死亡的起始、传播和最终执行的机制尚不清楚。在这里，我们表明铜含量在胃癌（GC）中显著升高，尤其是在恶性肿瘤中。筛选发现，METTL16 是一种非典型的甲基转移酶，通过 FDX1 mRNA 上的 mA 修饰，是铜死亡的关键介质。此外，铜应激促进 METTL16 在 K229 位点的乳酰化，随后引发铜死亡。SIRT2 抑制 METTL16 的乳酰化过程。升高的 METTL16 乳酰化显著提高了铜离子载体 elesclomol 的治疗效果。将 elesclomol 与 SIRT2 特异性抑制剂 AGK2 联合使用，可在体外和体内诱导胃肿瘤发生铜死亡。这些结果揭示了肿瘤中非组蛋白蛋白 METTL16 乳酰化在铜死亡中的重要性。鉴于 GC 中铜和乳酸盐浓度较高，诱导铜死亡成为 GC 的一种有前途的治疗策略。
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