Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27157, USA.
Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, Yongchuan, Chongqing 402160, China.
Cell Metab. 2023 Oct 3;35(10):1782-1798.e8. doi: 10.1016/j.cmet.2023.07.009. Epub 2023 Aug 15.
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 mC 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.
葡萄糖代谢被认为是肿瘤发生的关键因素。然而，葡萄糖是否作为一种信号分子，直接调节癌蛋白活性从而促进肿瘤发生，目前仍不清楚。在这里，我们报告葡萄糖是一种辅因子，可与甲基转移酶 NSUN2 结合在氨基酸 1-28 处，促进 NSUN2 寡聚化和激活。NSUN2 的激活维持了全局 mC RNA 甲基化，包括 TREX2，并稳定了 TREX2，以限制细胞质 dsDNA 的积累和 cGAS/STING 的激活，从而促进肿瘤发生和抗 PD-L1 免疫治疗耐药。一个 NSUN2 突变体，其葡萄糖结合缺陷或破坏葡萄糖/NSUN2 相互作用，会导致 NSUN2 活性和 TREX2 诱导的丧失，从而引发 cGAS/STING 的激活，抑制肿瘤发生。引人注目的是，通过激活 cGAS/STING 促进细胞凋亡和 CD8 T 细胞浸润，遗传删除葡萄糖/NSUN2/TREX2 轴可抑制冷肿瘤的肿瘤发生并克服抗 PD-L1 免疫治疗耐药性。我们的研究确定了 NSUN2 作为一种直接的葡萄糖传感器，其通过葡萄糖激活来驱动肿瘤发生和免疫治疗耐药性，从而维持 TREX2 的表达以抑制 cGAS/STING 的激活。
