NEDDylation是一种与泛素化具有高度相似性的蛋白质翻译后修饰类型。UBE1C编码NEDDylation E1酶，位于染色质区域3p14.1，并在亚洲和高加索肺癌患者中显示出高基因多倍体扩增频率。然而，其NEDDylation底物和在肿瘤发生中的作用尚未阐明。本研究旨在研究UBE1C的致癌作用以及其在NEDDylation调节p53在肺癌中的参与。我们发现UBE1C mRNA过表达和DNA扩增在大多数肺细胞系和癌症患者中均存在。UBE1C过表达的患者显示预后不良。此外，我们证明UBE1C和NEDD8（NEDDylation基团）的过表达导致p53的NEDDylation，并抑制K373残基的p53乙酰化。重要的是，UBE1C介导的NEDDylation通过抑制p53靶向其下游转录靶点的启动子区域的能力，降低了p53的转录活性，从而抑制了p53下游基因（包括p21和PTEN）的启动子活性以及mRNA和蛋白质的表达。此外，UBE1C和NEDD8的过表达促进了肺癌细胞的迁移、侵袭和增殖。我们的发现表明UBE1C作为一个具有预后潜能的致癌基因，并强调了在肺癌中UBE1C介导的NEDDylation在下调p53转录活性方面的潜在作用。© 2023 Federation of American Societies for Experimental Biology.

NEDDylation is a type of protein post-translational modification that has high similarity to ubiquitination. UBE1C encodes NEDDylation E1 enzyme, locates at chromatin region 3p14.1 and shows high gene dosage amplification frequency in both Asian and Caucasian lung cancer patients. However, its NEDDylation substrates and roles in tumorigenesis remain elucidated. In this study, we aim to investigate the oncogenic role of UBE1C and its involvement in how NEDDylation regulates p53 in lung cancer. We found that UBE1C mRNA overexpression and DNA amplification in most of the lung cell lines and cancer patients. Patients with UBE1C overexpression showed poor prognosis. Moreover, we demonstrated that overexpression of UBE1C and NEDD8, a NEDDylation moiety, resulted in the p53 NEDDylation with inhibition of p53 acetylation at K373 residue. Importantly, UBE1C-mediated NEDDylation downregulated the transcriptional activity of p53 by inhibiting p53 ability to target promoter regions of its downstream transcription targets, consequently inhibiting the promoter activities and the expression of mRNA and protein of the p53 downstream genes including p21 and PTEN. In addition, UBE1C and NEDD8 overexpression promoted migration, invasion, and proliferation of lung cancer cells. Our findings suggest that UBE1C acts as an oncogene with prognostic potential and highlight a potential role of UBE1C-mediated NEDDylation in downregulation of p53 transcriptional activity in lung cancer.© 2023 Federation of American Societies for Experimental Biology.