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Review
. 2025 Jan 7;14(2):69.
doi: 10.3390/cells14020069.

Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities

Aiman B Awan  1 , Maryiam Jama Ali Osman  1   2 , Omar M Khan  1
Affiliations
Review

Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities

Aiman B Awan et al. Cells. .

Abstract

Ubiquitination is cells' second most abundant posttranslational protein modification after phosphorylation. The ubiquitin-proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development and spread of multiple cancers since several of the UPS family members possess oncogenic or tumor suppressor activities. This comprehensive review delves into understanding the ubiquitin code, shedding light on its role in cancer cell biology and immune evasion. Furthermore, we highlighted recent advances in the field for targeting the UPS pathway members for effective therapeutic intervention against human cancers. We also discussed the recent update on small-molecule inhibitors and PROTACs and their progress in preclinical and clinical trials.

Keywords: E3 ligases; PROTACs; cancer; cell cycle; immune evasion; oncogenes; tumor suppressor; ubiquitination.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The ubiquitination cascade. A ubiquitin molecule is first charged by the E1 enzyme at the expense of an ATP molecule. The charged ubiquitin is then transferred to the E2 via a transthiolation reaction. E2 collaborates with E3 ubiquitin ligase, which adds ubiquitin to the protein substrate. A polyubiquitinated substrate is recognized by the proteasome machinery, where the substrate is degraded, and ubiquitin is recycled. Created with BioRender.com.
Figure 2
Figure 2
Types of ubiquitination. (a) A single ubiquitin is attached to the substrate protein. (b) Several ubiquitin molecules are attached to multiple lysine residues within the same protein. (c) The same type of ubiquitination is used throughout a single polyubiquitin chain. (d) More than two different types of ubiquitin linkages are used in a polyubiquitin chain. (e) A single ubiquitin is used for two or more ubiquitin attachments subsequently. Created with BioRender.com.
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