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.

中文翻译：

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有效靶向泛素样修饰剂NEDD8以治疗肺腺癌。

蛋白质融合作用是将表达的神经前体细胞与发育相关的8（NEDD8）结合到基底上的过程，在肺癌的致癌作用中起着促进肿瘤的作用。我们以前的研究表明，MLN4924是NEDD8活化酶（E1）的抑制剂，可显着抑制多种癌细胞的生长。但是，耐药性可能会因突变而发展成对MLN4924的抵抗力。因此，重要的是进一步了解NEDD8在肺癌中的作用。在本研究中，我们证明NEDD8在肺癌中过度活化，使患者的总体生存期更差。此外，我们报道，在肺腺癌细胞中，NEDD8耗竭显着抑制了肺癌细胞的体外和体内生长。₂期，因此以细胞系依赖性方式诱导凋亡或衰老。本研究证明NEDD8在调节肺癌细胞恶性表型中的作用，并进一步证实NEDD8是肺癌的潜在治疗靶标。