接合作用
卡林
细胞周期
泛素连接酶
细胞生长
癌症研究
化学
细胞生物学
蛋白质降解
泛素
细胞周期检查点
NEDD8公司
细胞
生物
生物化学
基因
作者
Yihan Ma,Xucheng Huang,Yanzhong Wang,Yinjiao Lei,Jinpu Yu,Shuxun Yu,Yinghong Gao,Jun Yang,Feng Zhu,Haitao Yu,Jin Zeng,Yong Chu,Min Yang,Guoli Li,Xinyou Xie,Jun Zhang
标识
DOI:10.1002/advs.202305907
摘要
Abstract Cell cycle dysregulation is a defining feature of breast cancer. Here, 1‐methyl‐nicotinamide (1‐MNA), metabolite of nicotinamide N‐methyltransferase(NNMT) is identified, as a novel driver of cell‐cycle progression in breast cancer. NNMT, highly expressed in breast cancer tissues, positively correlates with tumor grade, TNM stage, Ki‐67 index, and tumor size. Ablation of NNMT expression dramatically suppresses cell proliferation and causes cell‐cycle arrest in G0/G1 phase. This phenomenon predominantly stems from the targeted action of 1‐MNA, resulting in a specific down‐regulation of p27 protein expression. Mechanistically, 1‐MNA expedites the degradation of p27 proteins by enhancing cullin‐1 neddylation, crucial for the activation of Cullin‐1‐RING E3 ubiquitin ligase(CRL1)—an E3 ubiquitin ligase targeting p27 proteins. NNMT/1‐MNA specifically up‐regulates the expression of UBC12, an E2 NEDD8‐conjugating enzyme required for cullin‐1 neddylation. 1‐MNA showes high binding affinity to UBC12, extending the half‐life of UBC12 proteins via preventing their localization to lysosome for degradation. Therefore, 1‐MNA is a bioactive metabolite that promotes breast cancer progression by reinforcing neddylation pathway‐mediated p27 degradation. The study unveils the link between NNMT enzymatic activity with cell‐cycle progression, indicating that 1‐MNA may be involved in the remodeling of tumor microenvironment.
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