Abstract
Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and, eventually, metastasis. The attachment of ubiquitin signals by E3 ubiquitin ligases is directly opposed by the action of approximately 100 deubiquitinating enzymes (DUBs) in humans. Together, DUBs and E3 ligases coordinate ubiquitin signalling by providing selectivity for different substrates and/or ubiquitin signals. The balance between ubiquitination and deubiquitination is exquisitely controlled to ensure properly coordinated proteostasis and response to cellular stimuli and stressors. Not surprisingly, then, DUBs have been associated with all hallmarks of cancer. These relationships are often complex and multifaceted, highlighted by the implication of multiple DUBs in certain hallmarks and by the impact of individual DUBs on multiple cancer-associated pathways, sometimes with contrasting cancer-promoting and cancer-inhibiting activities, depending on context and tumour type. Although it is still understudied, the ever-growing knowledge of DUB function in cancer physiology will eventually identify DUBs that warrant specific inhibition or activation, both of which are now feasible. An integrated appreciation of the physiological consequences of DUB modulation in relevant cancer models will eventually lead to the identification of patient populations that will most likely benefit from DUB-targeted therapies.
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Acknowledgements
The authors thank S. Devine for help with compound structures. G.D. is supported by a fellowship from the Bodhi Education Foundation and grants from the National Health and Medical Research Council Australia (GNT2001406, GNT2004446). P.J.A.E.’s research was carried out during the tenure of a research project grant from Cancer Council Western Australia (CCWA 2022/1165) and WANMA (WANMA2021/7 Eichhorn). D.K. is supported by the National Health and Medical Research Council Australia (GNT1178122). The authors thank A. Wylie (KSQ Therapeutics, Cambridge, MA, USA) for sharing unpublished insights on KSQ-4279. This work was supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000587) and the Victorian State Government Operational Infrastructure Support, Australia. The authors apologize to authors whose relevant work was not discussed due to space constraints.
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G.D. and D.K. are employees of the Walter and Eliza Hall Institute of Medical Research, which receives milestone payments for Venclexta (venetoclax). D.K. is founder and shareholder of Entact Bio. P.J.A.E. declares no competing interests.
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Supplementary information
Glossary
- Alternative lengthening of telomeres
-
(ALT). A mechanism to limit degradation of telomeres that is independent of telomerase.
- Autophagosome
-
A double-membrane structure encapsulating autophagy cargo.
- Autophagy
-
The clearance of organelles or protein aggregates through lysosomal degradation.
- BH3 mimetics
-
Small molecules designed to mimic the activity of BH3-only proteins in binding pro-survival BCL-2 proteins.
- Condensate formation
-
The membrane-less compartmentalization of biomolecules driven by changes in solubility.
- Degron
-
A minimal protein signal for target protein degradation.
- E3 ubiquitin ligase enzymes
-
Enzymes that catalyse the transfer of ubiquitin to substrates.
- Fanconi anaemia DNA repair pathway
-
A multi-protein pathway to repair DNA inter-strand cross-links.
- Glutaminolysis
-
The conversion of glutamine into carbon sources for the TCA cycle.
- Hypomorphic variants
-
Amino acid substitutions that reduce, but do not block, protein function.
- Isopeptide bonds
-
A type of covalent bond between the carboxyl group of one amino acid and the amino group of another.
- Lipid peroxidation
-
The oxidative damage of lipids.
- Lysosome
-
Membrane-bound organelles containing enzymes to breakdown biomolecules, including protein and nucleic acids.
- Mitophagy
-
The autophagy of mitochondria.
- Non-homologous recombination
-
An error-prone DNA double strand break repair mechanism.
- Nucleotide excision repair
-
The bulk removal of mutagen-induced DNA lesions.
- Peroxisomes
-
An organelle that performs metabolic reactions and detoxifies oxygen species.
- Proteasome
-
A multisubunit machine for the selective degradation of proteins.
- Scissile bond
-
A covalent bond that can be broken by an enzyme.
- Spindle checkpoint
-
A complex that ensures proper segregation of duplicate chromosomes during mitosis or meiosis.
- Synthetic lethality
-
Mutations or alterations in multiple genes that are lethal when in combination, but not alone.
- Telomerase
-
An enzyme that adds repetitive sequence to telomeres to maintain telomere length at chromosome ends.
- Translesion synthesis
-
DNA synthesis across a lesion to avoid DNA replication failure.
- Unfoldases
-
Enzymes that promote protein unfolding.
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Dewson, G., Eichhorn, P.J.A. & Komander, D. Deubiquitinases in cancer. Nat Rev Cancer 23, 842–862 (2023). https://doi.org/10.1038/s41568-023-00633-y
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DOI: https://doi.org/10.1038/s41568-023-00633-y
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