Deubiquitinases in cancer.
Journal
Nature reviews. Cancer
ISSN: 1474-1768
Titre abrégé: Nat Rev Cancer
Pays: England
ID NLM: 101124168
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
accepted:
21
09
2023
medline:
24
11
2023
pubmed:
8
11
2023
entrez:
7
11
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37935888
doi: 10.1038/s41568-023-00633-y
pii: 10.1038/s41568-023-00633-y
doi:
Substances chimiques
Ubiquitin
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Deubiquitinating Enzymes
EC 3.4.19.12
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
842-862Informations de copyright
© 2023. Springer Nature Limited.
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pubmed: 27432896
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pmcid: 5896202
pubmed: 29576527
Haahr, P. et al. ZUFSP deubiquitylates K63-linked polyubiquitin chains to promote genome stability. Mol. Cell 70, 165–174 e166 (2018). Together with Kwasna et al. (2018), this study reveals a role for the previously uncharacterized DUB ZUP1 in maintaining genomic integrity through its ability to cleave Lys63-linked chains.
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Lange, S. M., Armstrong, L. A. & Kulathu, Y. Deubiquitinases: from mechanisms to their inhibition by small molecules. Mol. Cell 82, 15–29 (2022).
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Liu, J. et al. TF-DUBTACs stabilize tumor suppressor transcription factors. J. Am. Chem. Soc. 144, 12934–12941 (2022).
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Worden, E. J., Padovani, C. & Martin, A. Structure of the Rpn11–Rpn8 dimer reveals mechanisms of substrate deubiquitination during proteasomal degradation. Nat. Struct. Mol. Biol. 21, 220–227 (2014).
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pmcid: 9117149
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pmcid: 2577292
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Ernst, R., Mueller, B., Ploegh, H. L. & Schlieker, C. The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER. Mol. Cell 36, 28–38 (2009).
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pmcid: 1440312
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Atanassov, B. S. et al. ATXN7L3 and ENY2 coordinate activity of multiple H2B deubiquitinases important for cellular proliferation and tumor growth. Mol. Cell 62, 558–571 (2016).
pmcid: 4874879
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Morgan, M. T. et al. Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science 351, 725–728 (2016).
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Atanassov, B. S. & Dent, S. Y. USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1. EMBO Rep. 12, 924–930 (2011).
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pmcid: 3941643
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Ji, L. et al. USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of axin. Nat. Commun. 10, 4184 (2019).
pmcid: 6744515
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Bushman, J. W. et al. Proteomics-based identification of DUB substrates using selective inhibitors. Cell Chem. Biol. 28, 78–87 e73 (2021). This important paper for the clinical translation of DUB inhibitors develops DUB inhibitor treatment coupled to mass spectrometry to profile DUB substrates.
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Steger, M. et al. Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale. Nat. Commun. 12, 5399 (2021).
pmcid: 8438043
pubmed: 34518535
Clancy, A. et al. The deubiquitylase USP9X controls ribosomal stalling. J. Cell Biol. 220, e202024211 (2021). This paper identifies an important role for USP9X in ribosomal stalling that may explain its importance in tumour settings.
Diefenbacher, M. E. et al. Usp28 counteracts Fbw7 in intestinal homeostasis and cancer. Cancer Res. 75, 1181–1186 (2015).
pmcid: 4384988
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Diefenbacher, M. E. et al. The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer. J. Clin. Invest. 124, 3407–3418 (2014).
pmcid: 4109555
pubmed: 24960159
Wang, X. et al. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci. Rep. 6, 26979 (2016).
pmcid: 4893612
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Rowinsky, E. K. et al. Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma. Invest. New Drugs 38, 1448–1453 (2020).
pmcid: 7497669
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Ward, J. A. et al. Re-evaluating the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein cross-linking with michael acceptor motif-containing drugs. J. Med. Chem. 63, 3756–3762 (2020).
pmcid: 7152998
pubmed: 32109059