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.
[1]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Canc Inst, Shanghai 200032, Peoples R China.
[2]Fudan Univ, Shanghai Canc Ctr, Canc Inst, Shanghai 200032, Peoples R China.
[3]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China.
[4]Zhejiang Univ, Sch Med, Inst Translat Med, Hangzhou 30029, Zhejiang, Peoples R China.
[5]Univ Michigan, Dept Radiat Oncol, Div Radiat & Canc Biol, 1301 Catherine St, Ann Arbor, MI 48109 USA.
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