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Proteasome-associated deubiquitinases and cancer

Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysi...

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Published in:Cancer and metastasis reviews 2017-12, Vol.36 (4), p.635-653
Main Authors: Mofers, Arjan, Pellegrini, Paola, Linder, Stig, D’Arcy, Pádraig
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description Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
doi_str_mv 10.1007/s10555-017-9697-6
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subjects Addictions
Apoptosis
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer och onkologi
Cancer Research
Cell- och molekylärbiologi
Delivery services
Deregulation
Development and progression
Homeostasis
Inhibitors
Klinisk medicin
Ligases
Medicin och hälsovetenskap
Medicinska och farmaceutiska grundvetenskaper
Multiple myeloma
Oncology
Proteasome inhibitors
Protein biosynthesis
Protein folding
Protein synthesis
Proteins
Proteolysis
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
title Proteasome-associated deubiquitinases and cancer
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