NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.
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2023-10
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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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Chen, Tingjin, Zhi-Gang Xu, Jie Luo, Rajesh Kumar Manne, Zhengyu Wang, Che-Chia Hsu, Bo-Syong Pan, Zhen Cai, et al. (2023). NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell metabolism, 35(10). pp. 1782–1798.e8. 10.1016/j.cmet.2023.07.009 Retrieved from https://hdl.handle.net/10161/33825.
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Scholars@Duke
RAJESHKUMAR MANNE
Che-Chia Hsu
My research has focused on mitochondrial functions in cancer metabolism and understand the role of mitochondrial dynamics in cellular function and human diseases including cancers. Additionally, I also continuously dissect cancer metabolism and identifying potential metabolic vulnerabilities of cancer initiation, progression and metastasis using several in vitro, ex vivo and in vivo genetical approaches such as CRISPR/Cas9 knockout, mouse/ human organoid cultures and genetically engineered mouse models, thereby characterizing molecular mechanisms regulated by metabolic pathways and developing potential metabolic interventions for targeting cancers.
Hui-Kuan Lin
The research interest in Dr. Lin lab is to understand oncogenic networks between oncogenes and tumor suppressor genes, dissect the regulatory mechanisms underlying the crosstalk between ageing and cancer, to unravel the role of posttranslational modifications (PTMs) such as ubiquitination and metabolism in diverse molecular and biological processes important for cancer progression and metastasis, cancer stem regulation, cancer immunity and drug resistance by using biochemical and molecular approaches along with and genetic mouse models, and finally to develop small molecule inhibitors and antibodies targeting critical oncogenic signaling and metabolic vulnerabilities for cancer treatment. His research goals aim to not only reveal fundamental insights and concepts for cancer biology and cancer immunity, but also develop novel paradigms and therapeutic strategies for targeting human cancer and overcoming drug resistance.
Research interests include:
- Crosstalk between oncogenic and tumor suppressor networks
- Posttranslational modifications in signaling and cancer
- Cancer progression and metastasis
- Biology of normal and cancer stem cells
- Metabolism in cancer and ageing
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