Skip to main content
Journal cover image

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Publication ,  Journal Article
Chen, T; Xu, Z-G; Luo, J; Manne, RK; Wang, Z; Hsu, C-C; Pan, B-S; Cai, Z; Tsai, P-J; Tsai, Y-S; Chen, Z-Z; Li, H-Y; Lin, H-K
Published in: Cell Metab
October 3, 2023

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

October 3, 2023

Volume

35

Issue

10

Start / End Page

1782 / 1798.e8

Location

United States

Related Subject Headings

  • Signal Transduction
  • Nucleotidyltransferases
  • Methyltransferases
  • Immunotherapy
  • Humans
  • Endocrinology & Metabolism
  • Carcinogenesis
  • 3205 Medical biochemistry and metabolomics
  • 3101 Biochemistry and cell biology
  • 1101 Medical Biochemistry and Metabolomics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chen, T., Xu, Z.-G., Luo, J., Manne, R. K., Wang, Z., Hsu, C.-C., … Lin, H.-K. (2023). NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab, 35(10), 1782-1798.e8. https://doi.org/10.1016/j.cmet.2023.07.009
Chen, Tingjin, Zhi-Gang Xu, Jie Luo, Rajesh Kumar Manne, Zhengyu Wang, Che-Chia Hsu, Bo-Syong Pan, et al. “NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.Cell Metab 35, no. 10 (October 3, 2023): 1782-1798.e8. https://doi.org/10.1016/j.cmet.2023.07.009.
Chen T, Xu Z-G, Luo J, Manne RK, Wang Z, Hsu C-C, et al. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab. 2023 Oct 3;35(10):1782-1798.e8.
Chen, Tingjin, et al. “NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.Cell Metab, vol. 35, no. 10, Oct. 2023, pp. 1782-1798.e8. Pubmed, doi:10.1016/j.cmet.2023.07.009.
Chen T, Xu Z-G, Luo J, Manne RK, Wang Z, Hsu C-C, Pan B-S, Cai Z, Tsai P-J, Tsai Y-S, Chen Z-Z, Li H-Y, Lin H-K. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab. 2023 Oct 3;35(10):1782-1798.e8.
Journal cover image

Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

October 3, 2023

Volume

35

Issue

10

Start / End Page

1782 / 1798.e8

Location

United States

Related Subject Headings

  • Signal Transduction
  • Nucleotidyltransferases
  • Methyltransferases
  • Immunotherapy
  • Humans
  • Endocrinology & Metabolism
  • Carcinogenesis
  • 3205 Medical biochemistry and metabolomics
  • 3101 Biochemistry and cell biology
  • 1101 Medical Biochemistry and Metabolomics