Protein neddylation and its alterations in human cancers for targeted therapy.

Neddylation, a post-translational modification that conjugates an ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. The best-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), which, as the largest family of E3 ubiquitin ligases, control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. Recently, increasing pieces of experimental evidence strongly indicate that the process of protein neddylation modification is elevated in multiple human cancers, providing sound rationale for its targeting as an attractive anticancer therapeutic strategy. Indeed, neddylation inactivation by MLN4924 (also known as pevonedistat), a small molecule inhibitor of E1 NEDD8-activating enzyme currently in phase I/II clinical trials, exerts significant anticancer effects by inducing cell cycle arrest, apoptosis, senescence and autophagy in a cell-type and context dependent manner. Here, we summarize the latest progresses in the field with a major focus on preclinical studies in validation of neddylation modification as a promising anticancer target.

Zhou L ，Zhang W ，Sun Y ，Jia L ... -  《-》

Targeting Protein Neddylation for Cancer Therapy.

Zhou L ，Jia L 《-》

Suppression of tumor angiogenesis by targeting the protein neddylation pathway.

Yao WT ，Wu JF ，Yu GY ，Wang R ，Wang K ，Li LH ，Chen P ，Jiang YN ，Cheng H ，Lee HW ，Yu J ，Qi H ，Yu XJ ，Wang P ，Chu YW ，Yang M ，Hua ZC ，Ying HQ ，Hoffman RM ，Jeong LS ，Jia LJ ... -  《Cell Death & Disease》

Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells.

Lan H ，Tang Z ，Jin H ，Sun Y ... -  《Scientific Reports》

A first-in-class inhibitor, MLN4924 (pevonedistat), induces cell-cycle arrest, senescence, and apoptosis in human renal cell carcinoma by suppressing UBE2M-dependent neddylation modification.

Xu B ，Deng Y ，Bi R ，Guo H ，Shu C ，Shah NK ，Chang J ，Liu G ，Du Y ，Wei W ，Wang C ... -  《-》