NSUN2, also known as NOP2/Sun RNA methyltransferase family member 2, is a key enzyme in 5-methylcytosine (m5C) RNA modification. It methylates various RNA species such as tRNAs, mRNAs, and non-coding RNAs, influencing RNA stability, translation efficiency, and cellular stress responses. This modification impacts cell proliferation, differentiation, and survival, and NSUN2 is thus of great biological importance in processes like tumorigenesis [4].

Genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in "cold" tumors. This shows that NSUN2, activated by glucose, drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation [1]. In EGFR-mutant non-small-cell lung cancer, genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib [2]. In gastric cancer, knockdown of NSUN2-modified by SUMO-2/3 affects m5C-methylated genes involved in cancer-related signaling pathways [3]. In endometrial cancer, knockdown of NSUN2 increases susceptibility to ferroptosis [5]. In osteosarcoma, knocking down NSUN2 expression counterbalances its promoting effect on cancer progression [6]. In esophageal squamous cell carcinoma, silencing NSUN2 suppresses tumorigenesis and progression in Nsun2 knockout mouse models [7].

In summary, NSUN2-mediated m5C RNA modification plays a crucial role in multiple biological processes, especially in tumor-related mechanisms. Gene knockout and conditional knockout mouse models have been instrumental in revealing NSUN2's role in tumorigenesis, immunotherapy resistance, and drug resistance in various cancers, providing potential therapeutic targets for these diseases.

References:

1. Chen, Tingjin, Xu, Zhi-Gang, Luo, Jie, Li, Hong-Yu, Lin, Hui-Kuan. 2023. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. In Cell metabolism, 35, 1782-1798.e8. doi:10.1016/j.cmet.2023.07.009. https://pubmed.ncbi.nlm.nih.gov/37586363/

2. Wang, Yueqin, Wei, Jingyao, Feng, Luyao, Kan, Quancheng, Tian, Xin. 2023. Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer. In Molecular cancer, 22, 81. doi:10.1186/s12943-023-01780-4. https://pubmed.ncbi.nlm.nih.gov/37161388/

3. Hu, Yuanbo, Chen, Chenbin, Tong, Xinya, Xue, Xiangyang, Lu, Mingdong. 2021. NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation. In Cell death & disease, 12, 842. doi:10.1038/s41419-021-04127-3. https://pubmed.ncbi.nlm.nih.gov/34504059/

4. Li, Penghui, Huang, Di. 2024. NSUN2-mediated RNA methylation: Molecular mechanisms and clinical relevance in cancer. In Cellular signalling, 123, 111375. doi:10.1016/j.cellsig.2024.111375. https://pubmed.ncbi.nlm.nih.gov/39218271/

5. Chen, Shuai-Jun, Zhang, Jun, Zhou, Ting, Wei, Si-Tian, Zhang, Hong-Feng. 2023. Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA. In Redox biology, 69, 102975. doi:10.1016/j.redox.2023.102975. https://pubmed.ncbi.nlm.nih.gov/38042059/

6. Yang, Min, Wei, Renxiong, Zhang, Sheng, Cai, Lin, Xie, Yuanlong. 2023. NSUN2 promotes osteosarcoma progression by enhancing the stability of FABP5 mRNA via m5C methylation. In Cell death & disease, 14, 125. doi:10.1038/s41419-023-05646-x. https://pubmed.ncbi.nlm.nih.gov/36792587/

7. Su, Jiachun, Wu, Guandi, Ye, Ying, Lin, Dongxin, Zheng, Jian. 2021. NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization. In Oncogene, 40, 5814-5828. doi:10.1038/s41388-021-01978-0. https://pubmed.ncbi.nlm.nih.gov/34345012/