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Cited by 70Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysCancer-related Molecular Pathways

Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy

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Liu, Ting-Ting, Yang, Heng, Zhuo, Fang-Fang, Yang, Zhuo, Zhao, Mei-Mei, Guo, Qiang, Liu, Yang, Liu, Dan +2 more·2022·eBioMedicine
DOI 10.1016/j.ebiom.2022.104353PMC PMC9667253
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Abstract

BACKGROUND: The E2F family of transcription factors play a crucial role in the development of various cancers. However, E2F members lack targetable binding pockets and are typically considered "undruggable". Unlike canonical small-molecule therapeutics, molecular glues mediate new E3 ligase-protein interactions to induce selective proteasomal degradation, which represents an attractive option to overcome these limitations. METHODS: Human proteome microarray was utilized to identify a natural product-derived molecular glue for targeting E2F2 degradation. Co-IP analysis with stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics was carried out to further explore the E3 ligase for E2F2 degradation. FINDINGS: In this study, we identified a molecular glue bufalin, which significantly promoted E2F2 degradation. Unexpectedly, E2F2 underwent ubiquitination and proteasomal degradation via a previously undisclosed atypical E3 ligase, zinc finger protein 91 (ZFP91). In particular, we observed that bufalin markedly promoted E2F2-ZFP91 complex formation, thereby leading to E2F2 polyubiquitination via K48-linked ubiquitin chains for degradation. E2F2 degradation subsequently caused transcriptional suppression of multiple oncogenes including c-Myc, CCNE1, CCNE2, MCM5 and CDK1, and inhibited hepatocellular carcinoma growth in vitro and in vivo. INTERPRETATION: Collectively, our findings open up a new direction for transcription factors degradation by targeting atypical E3 ligase ZFP91. Meanwhile, the chemical knockdown strategy with molecular glue may promote innovative transcription factor degrader development in cancer therapy. FUNDING: This work was financially supported by the National Key Research and Development Project of China (2022YFC3501601), National Natural Sciences Foundation of China (81973505, 82174008, 82030114), and China Postdoctoral Science Foundation (2019M650396), the Fundamental Research Funds for the Central Universities.

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Cited by

Sorted by citations

Authors
Liu, T.-T., Yang, H., Zhuo, F.-F., Yang, Z., Zhao, M.-M., Guo, Q., Liu, Y., Liu, D., Zeng, K.-W., & Tu, P.-F.
Affiliations
Peking University (CN)
Corresponding author
Zeng, Ke-Wu
ORCID
Venue
eBioMedicine
Publisher
Elsevier BV
Published
2022-12
Volume
86
Pages
104353
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2022.104353
PMC
PMC9667253
OpenAlex
W4308929210
Cited by
70
References
1
Citations by year
2026: 21 · 2025: 21 · 2024: 18 · 2023: 9 · 2022: 1
FWCI
4.00
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81973505, 82030114, 82174008)
  • China Postdoctoral Science Foundation (2019M650396)
  • National Key Research and Development Program of China (2022YFC3501601)
  • Fundamental Research Funds for the Central Universities
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
E2F2, molecular glues, bufalin, E3 ubiquitin ligase, proteasomal degradation, transcription factor degradation, K48-linked ubiquitination, hepatocellular carcinoma, c-Myc, cyclin E1, cyclin E2, MCM5, CDK1, natural product drug discovery
MeSH terms
Bufanolides, Humans, Neoplasms, Transcription Factors, Ubiquitin-Protein Ligases, E2F2 Transcription Factor, Ubiquitination, Proteolysis

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