Abstract
Up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.
概要
目的
UPF1是调节无义介导的mRNA降解的核心因子,参与多种肿瘤进展相关分子通路的调节,其在肺腺癌氨基酸代谢中的作用尚不清楚。
方法和结果
本研究通过结合生物信息学和代谢组学,分析发现UPF1与肺腺癌中部分氨基酸代谢通路显著相关,证实UPF1敲低后可显著抑制氨基酸代谢重编程核心蛋白ATF4的表达及eIF2α-Ser51位点的磷酸化水平,且UPF1通过调控ATF4蛋白增加肺腺癌细胞的氨基酸水平进而促进细胞增殖。在临床患者样本数据库中,肺腺癌组织中UPF1的mRNA水平表达异常,UPF1和ATF4均高表达的肺腺癌患者有着较差的总生存期。
结论
本研究表明,UPF1是肿瘤氨基酸代谢重编程的潜在调控因子,可作为肺腺癌治疗的新靶点。
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81803886, 81774078, and 21907093). We thank members of the Dr. Hailong PIAO laboratory (Group 1821, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China) for helpful discussion.
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Lei FANG, Huan QI, and Peng WANG conceived the project, and designed and performed most of experiments and the data analysis. Hailong PIAO and Chundong GU supervised the project. Lei FANG and Shiqing WANG performed the establishment of animal models. Lei FANG, Huan QI, and Tianjiao LI provided significant intellectual input. Lei FANG, Huan QI, and Tian XIA wrote the manuscript with input from all other authors. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, and Chundong GU declare that they have no conflict of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed. All animal care and experimental procedures were approved by the Animal Care Ethics and Use Committee of Dalian Medical University (No. AEE19015).
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Fang, L., Qi, H., Wang, P. et al. UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis. J. Zhejiang Univ. Sci. B 23, 863–875 (2022). https://doi.org/10.1631/jzus.B2200144
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DOI: https://doi.org/10.1631/jzus.B2200144
Key words
- Up-frameshift 1 (UPF1)
- Activating transcription factor 4 (ATF4)
- Amino acid metabolism
- Lung adenocarcinoma