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Review
. 2021 Apr 7;14(1):57.
doi: 10.1186/s13045-021-01070-w.

Targeting neddylation E2s: a novel therapeutic strategy in cancer

Yi-Chao Zheng  1 , Yan-Jia Guo  1 , Bo Wang  1 , Chong Wang  2 , M A A Mamun  1 , Ya Gao  3 , Hong-Min Liu  4
Affiliations
Review

Targeting neddylation E2s: a novel therapeutic strategy in cancer

Yi-Chao Zheng et al. J Hematol Oncol. .

Abstract

Ubiquitin-conjugating enzyme E2 M (UBE2M) and ubiquitin-conjugating enzyme E2 F (UBE2F) are the two NEDD8-conjugating enzymes of the neddylation pathway that take part in posttranslational modification and change the activity of target proteins. The activity of E2 enzymes requires both a 26-residue N-terminal docking peptide and a conserved E2 catalytic core domain, which is the basis for the transfer of neural precursor cell-expressed developmentally downregulated 8 (NEDD8). By recruiting E3 ligases and targeting cullin and non-cullin substrates, UBE2M and UBE2F play diverse biological roles. Currently, there are several inhibitors that target the UBE2M-defective in cullin neddylation protein 1 (DCN1) interaction to treat cancer. As described above, this review provides insights into the mechanism of UBE2M and UBE2F and emphasizes these two E2 enzymes as appealing therapeutic targets for the treatment of cancers.

Keywords: Anticancer treatment; Neddylation; Therapeutic targets; UBE2F; UBE2M.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Overview of the neddylation pathway. a Impact of neddylation in cancers. b The process by which NEDD8 is conjugated to its substrates. NEDD8 is activated by an NAE in an ATP-dependent manner, transferred to E2 and then conjugated to a lysine residue of the substrate protein with the aid of E3 ligase. Then, NEDD8 is removed by a deneddylase from the substrate and recycled. c The C-terminal carboxylate of NEDD8 is conjugated to the active cysteine residue of the E2 enzyme in the catalysis of E1. The E2-NEDD8 conjugate reacts with a lysine residue on the substrate to form the NEDD8 linkage
Fig. 2
Fig. 2
Structural analysis of UBE2M and UBE2F. a Primary sequence map of UBE2M and UBE2F. b Structure of UBE2M (PDB 2NVU). c Structure of the NAE-UBE2M complex. The NAE contains NAE1 and UBA3 (PDB 2NVU). d Structure of UBE2F (PDB 2EDI). e Structure of the UBA3 and UBE2F complex (PDB 3FN1)
Fig. 3
Fig. 3
Cross-talk between the E2 and E3 [89]. UBE2M, a stress-inducible protein promoted by HIF-1α and AP-1, plays a dual role as an E2 for ubiquitylation and neddylation to degrade the UBE2F, leading to the inactivation of CRL5 mediated by CRL3
Fig. 4
Fig. 4
UBE2M and UBE2F in cancer. Inhibiting the activity of UBE2M and UBE2F can inhibit cell proliferation. UBE2M can promote cell cycle progression to induce cell growth by stabilizing β-catenin and activating the neddylation of cullin1-4. UBE2M can recruit RNF111 to disturb the CtIP-BRCA1 interaction and promote H4 protein ubiquitylation via the neddylation of RNF168 to regulate DNA repair. UBE2F can reduce the level of NOXA by triggering CRL5 and then inhibit apoptosis and induce cell growth
Fig. 5
Fig. 5
UBE2M-DCN1 inhibitors. a The crystal structure of the interaction between DCN1 and the UBE2M peptide is shown in yellow (PDB 3TDU). b–g Chemical structures of UBE2M-DCN1 inhibitors
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