Work

NEDD8-conjugating enzyme UBC12 as a novel therapeutic target in esophageal squamous cell carcinoma

Year: 2020

Type: article

Abstract: Esophageal squamous cell carcinoma (ESCC) is the major histologic subtype of esophageal cancer with high incidence and mortality. 1 However, few achievements have been made in the development of targeted drugs. 2 Neddylation, a reversible post-translational modification, attaches ubiquitin-like molecule NEDD8 to substrates in a three-step enzymatic reaction catalyzed by NEDD8-activating enzyme E1 (NAE, NAE1 and UBA3 heterodimer), NEDD8-conjugating enzyme E2s (UBE2M/UBC12 or UBE2F) and substrate-specific NEDD8-E3 ligases. 3 The best-characterized substrates of neddylation are cullin family proteins, the essential components of multiunit Cullin-RING ubiquitin ligases (CRLs). 4 Currently, the inhibition of cullin neddylation by targeting overactivated neddylation pathway has emerged as an attractive approach for anticancer therapy. 5 , 6 Our previous study reported that MLN4924, a specific inhibitor of NAE, significantly inhibited the tumor growth of ESCC by blocking cullin neddylation and inactivating CRLs activity. 7 However, recent studies found that MLN4924 treatment-emergent NAE mutations would confer the drug resistance. 8 , 9 Therefore, it is urgent to identify other neddylation enzymes (E2s or E3s) as alternative anticancer targets and develop novel anti-ESCC strategies.

Source: Signal Transduction and Targeted Therapy

DOI: 10.1038/s41392-020-00226-3