Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity
Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity
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DOI：
10.1016/j.ccell.2023.05.005
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发表时间：
2023-06-12
期刊：
影响因子：
50.3
通讯作者：
Wang, Ping
中科院分区：
文献类型：
--
作者：
Fang, Lan;Hao, Yun;Wang, Ping
环GMP-AMP合酶（cGAS）是胞质DNA的主要传感器，并激活I型干扰素信号传导，在抗肿瘤免疫中起重要作用。然而，目前尚不清楚cGAS介导的抗肿瘤活性是否受营养状况的影响。在这里，我们的研究报告说，蛋氨酸剥夺通过阻断其甲基化来增强cGAS活性，甲基化由甲基转移酶SUV 39 H1催化。我们进一步表明，甲基化以UHRF 1依赖的方式增强cGAS的染色质隔离。阻断cGAS甲基化增强cGAS介导的抗肿瘤免疫并抑制结直肠肿瘤发生。临床上，人类癌症中的cGAS甲基化与较差的诊断相关。因此，我们的研究结果表明，营养应激通过可逆甲基化促进cGAS活化，并提出了在癌症治疗中靶向cGAS甲基化的潜在治疗策略。
Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and sup-presses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prog-nosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.