Protein neddylation in lung tumorigenesis: Target validation and targeted therapy

Much akin to ubiquitylation, neddylation is catalyzed by a cascade of three enzymes: E1 NEDD8-activating enzyme, E2 NEDD8-conjugating enzyme (UBE2M or UBE2F), and E3 NEDD8 ligases. The best-known neddylation substrates are the members of cullin family, leading to the activation of Cullin-RING ligases, which regulate a variety of downstream biological processes largely via promoting ubiquitylation and subsequent proteasomal degradation of many key signaling proteins. Notably, neddylation enzymes and components of the Cullin-RING ligases are frequently altered in many human cancers and have been validated as promising cancer targets. As such, drug discovery efforts are underway to target neddylation-Cullin-RING ligases with a few selective small molecule inhibitors being advanced into various phases of clinical trials. This review firstly provides a brief introduction to neddylation, then focuses on lung cancer, and summarizes a wealth of current data showing how neddylation-Cullin-RING ligases are altered and affect the growth and survival of lung cancer cells, lung tumorigenesis, lung tumor microenvironment, and inflammatory response. A few reported small molecule inhibitors of neddylation enzymes as well as their activity against lung cancer cells are also summarized, and future perspectives with an ultimate goal of discovering effective treatment of lung cancer via targeting neddylation-Cullin-RING ligases are proposed.