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Review
. 2021 Mar 25;13(7):1513.
doi: 10.3390/cancers13071513.

Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

Chee Wai Fhu  1 , Azhar Ali  1
Affiliations
Review

Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

Chee Wai Fhu et al. Cancers (Basel). .

Abstract

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review.

Keywords: cancer; chemoresistance; dysregulation; inhibitors; therapy; ubiquitin proteasome system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of the ubiquitin proteasome system (UPS). The UPS cascade. Substrate protein is ubiquitinated through the sequential action of three enzymes. E1 binds to activated ubiquitin and is transferred to the ubiquitin-conjugating enzyme (E2). The E2 carries the activated ubiquitin to ubiquitin ligase (E3), which then facilitates the transfer of ubiquitin from E2 to a lysine residue in the target protein. Proteins can be modified with a single mono-ubiquitin molecule, or with ubiquitin chains of different lengths and linkage types. Substrate proteins modified with specific chains are recognized and subsequently degraded by the 26S proteasome. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrate proteins by removing mono-ubiquitination or by trimming or removing the ubiquitin chain. Typically, poly-ubiquitination has been associated with protein clearance through proteasomal degradation while mono-ubiquitination which involves the addition of a single ubiquitin moiety to the substrate protein affects cellular processes.
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