癌变
生物
细胞生物学
癌症研究
信号转导
生物化学
基因
作者
Tingjin Chen,Zhigang Xu,Juan Luo,Rajesh Kumar Manne,Zhengyu Wang,Che-Chia Hsu,Bo‐Syong Pan,Zhen Cai,Pei‐Jane Tsai,Yau‐Sheng Tsai,Zhongzhu Chen,Hongyu Li,Hui‐Kuan Lin
出处
期刊:Cell Metabolism
[Elsevier]
日期:2023-10-01
卷期号:35 (10): 1782-1798.e8
被引量:10
标识
DOI:10.1016/j.cmet.2023.07.009
摘要
Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.
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