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Cited by 744Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsCancer-related Molecular Pathways

The role of ubiquitination in tumorigenesis and targeted drug discovery

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Deng, Lu, Meng, Tong, Chen, Lei, Wei, Wenyi, Wang, Ping·2020·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-020-0107-0PMC PMC7048745
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Abstract

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the “quantity” and “quality” of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI‐219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.

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  • The ubiquitin-proteasome system controls core signaling factor abundance by selective degradation, mediates many processes in embryonic development, and aberrant UPS-dependent degradation is involved in carcinogenesis.

    “The ubiquitin-proteasome system (UPS) provides an essential way to control core signaling factor abundance by selective degradation, such that it mediates many processes in embryonic development, also aberrant regulations of UPS-dependent degradation are involved in different pathological processes especially carcinogenesis22,23.”

    From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [22]

    The UPS section describes protein degradation and links UPS dysfunction to cancer; the Oct4 and Sox2 ubiquitination sections give examples of selective degradation of core regulatory factors. The CSC stemness section mentions embryonic development and UPS-regulated stem-cell processes, but it does not establish the broader claim that the UPS mediates many processes in embryonic development. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Deng, L., Meng, T., Chen, L., Wei, W., & Wang, P.
Affiliations
  • Northwest A&F University (CN)
  • Tongji University (CN)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
  • Deng, Lu
  • Wang, Ping
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2020-02-29
Volume
5
Issue
1
Pages
11-11
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-020-0107-0
PMC
PMC7048745
OpenAlex
W3009097360
Cited by
744
References
38
Citations by year
2026: 82 · 2025: 149 · 2024: 193 · 2023: 118 · 2022: 96 · 2021: 86 · 2020: 19 · 2018: 1
FWCI
7.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation of China | Key Programme (31830053)
  • National Natural Science Foundation of China (81625019, 31801177, 81702659)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
ubiquitination, carcinogenesis, protein posttranslational modification, cancer metabolism, tumor microenvironment, cancer stem cells, proteasome inhibitors, E3 ubiquitin ligase, deubiquitinase, mTOR signaling, PTEN/AKT signaling, STING signaling, Wnt signaling, Hippo/YAP signaling, targeted cancer therapy
MeSH terms
Humans, Neoplasms, Neoplastic Stem Cells, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Tumor Microenvironment, Carcinogenesis

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