NEDD8-conjugating enzyme E2s: critical targets for cancer therapy

Abstract

NEDD8-conjugating enzymes, E2s, include the well-studied ubiquitin-conjugating enzyme E2 M (UBE2M) and the poorly characterized ubiquitin-conjugating enzyme E2 F (UBE2F). UBE2M and UBE2F have distinct and prominent roles in catalyzing the neddylation of Cullin or non-Cullin substrates. These enzymes are overexpressed in various malignancies, conferring a worse overall survival. Targeting UBE2M to influence tumor growth by either modulating several biological responses of tumor cells (such as DNA-damage response, apoptosis, or senescence) or regulating the anti-tumor immunity holds strong therapeutic potential. Multiple inhibitors that target the interaction between UBE2M and defective cullin neddylation protein 1 (DCN1), a co-E3 for neddylation, exhibit promising anti-tumor effects. By contrast, the potential benefits of targeting UBE2F are still to be explored. It is currently reported to inhibit apoptosis and then induce cell growth; hence, targeting UBE2F serves as an effective chemo-/radiosensitizing strategy by triggering apoptosis. This review highlights the most recent advances in the roles of UBE2M and UBE2F in tumor progression, indicating these E2s as two promising anti-tumor targets.

The Ubiquitin–Proteasome System in Tumor Metabolism

“…It can alter the interaction of substrates with DNA, RNA, or other proteins, alter enzyme activity, and modulate other modifications in the human body [ 22 ]. Neddylation is regulated by NEDD8 and the next enzymatic cascade response of E1(NAE1), E2 (UBC12), and E3 (Cullin-RING ligases); it causes oncogenic modifications by degrading the tumor suppressor proteins [ 23 ]. FAT10 is another Ubl used to modulate substrate degradation by directly binding to substrates; subsequently, FAT10 and its substrates degrade together [ 24 ].…”

Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner

“…In the future, it will be important to investigate which TCF/LEF regions and, more specifically, which amino acid residues are responsible for the KDM2A-mediated destabilization and whether these amino acid residues are mutated in certain types of cancer. Moreover, since abnormal neddylation is known to be associated with various cancers [54,55], it would be interesting to investigate whether TCF/LEF protein levels are also inversely correlated with high neddylation in these pathological states.…”

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

“…171 Similarly, the NEDD8-binding enzyme UBE2M also has been demonstrated to be upregulated in several types of cancer and associated with poor patient survival. 172 In 2019, our group used homogene time-resolved fluorescence (HTRF) assay to screen WS-291 (Figure 8) from our in-house compound library (∼15000 compounds with ∼5000 distinct scaffolds), which could effectively inhibit DCN1 (IC 50 = 5.8 μM). By further optimizing the structure of WS-291, WS-383 (Table 3, Figure 8) was discovered to effectively block the interaction between DCN1-UBC12 (IC 50 = 11 nM) and selectively inhibit Cul1/3 attachment, leading to the accumulation of p21, p27, and NRF2.…”

“…Among them, defective in Cullin neddylation 1 (DCN1) is an overexpressed E3 ubiquitin ligase in different types of cancers and is closely associated with cancer progression . Similarly, the NEDD8-binding enzyme UBE2M also has been demonstrated to be upregulated in several types of cancer and associated with poor patient survival …”