Abstract
Protein neddylation, a process of conjugating neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to substrates, plays a tumor-promoting role in lung carcinogenesis. Our previous study showed MLN4924, an inhibitor of NEDD8 activating enzyme (E1), significantly inhibits the growth of multiple cancer cells. However, resistance can develop to MLN4924 by mutation. Therefore, it is important to further understand how NEDD8 acts in lung cancer. In the present study, we demonstrated NEDD8 is overactivated in lung cancers and confers a worse patient overall survival. Furthermore, we report that in lung adenocarcinoma cells, NEDD8 depletion significantly suppressed lung cancer cell growth and progression both in vitro and in vivo. Mechanistic studies revealed that NEDD8 depletion induced the accumulation of a panel of tumor-suppressive cullin-RING ubiquitin ligase substrates (e.g., p21, p27, and Wee1) via blocking their degradation, triggering cell cycle arrest at G2 phase, thus inducing apoptosis or senescence in a cell-line-dependent manner. The present study demonstrates the role of NEDD8 in regulating the malignant phenotypes of lung cancer cells and further validates NEDD8 as a potential therapeutic target in lung cancer.
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Acknowledgments
This work was supported by the Chinese Ministry of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81625018, 81820108022, 81772459, 81572340, 81602072, 81772470, and 81702244), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), Program of Shanghai Academic/Technology Research Leader (18XD1403800), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001), and Shuguang Program supported by Shanghai Education Development Foundation (14SG07).
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LJJ conceived the general framework of this study. YYJ and LJJ designed the experiments. YYJ and WC performed the experiments. LHL, LSZ, YPL, WLC, WJZ, GAC, SWW, HZ, WJZ, GJ, MSW, YMZ, and RMH provided technical, material, or administrative support. YYJ and LJJ prepared the manuscript. YMZ, MSW, and LJJ supervised this study.
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Jiang, Y., Cheng, W., Li, L. et al. Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment. Cell Biol Toxicol 36, 349–364 (2020). https://doi.org/10.1007/s10565-019-09503-6
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DOI: https://doi.org/10.1007/s10565-019-09503-6