KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination
Abstract
Cullin 3 (Cul3)-family ubiquitin ligases use the BTB-domain-containing proteins for the recruitment of substrates, but the regulation of this family of ubiquitin ligases has not been completely understood. KLHL20 is a BTB-family protein and targets tumor suppressor promyelocytic leukemia protein (PML) and death-associated protein kinase (DAPK) to its kelch-repeat domain for ubiquitination and degradation. Here, we show that another BTB-kelch protein KLHL39 is recruited to the substrate-binding domain of KLHL20 but is not a substrate of Cul3-KLHL20 complex. Interestingly, KLHL39 does not bind Cul3 because of the absence of certain conserved residues in the BTB domain. Instead, KLHL39 blocks KLHL20-mediated ubiquitination of PML and DAPK by disrupting the binding of these substrates to KLHL20 as well as the binding of KLHL20 to Cul3. Through the two mechanisms, KLHL39 increases the stability of PML and DAPK. In human colon cancers, downregulations of KLHL39, PML and DAPK are associated with metastatic progression. Furthermore, preclinical data indicate that KLHL39 promotes colon cancer migration, invasion and survival in vitro and metastasis in vivo through a PML- and DAPK-dependent mechanism. Our study identifies KLHL39 as a negative regulator of Cul3-KLHL20 ubiquitin ligase and reveals a role of KLHL39-mediated PML and DAPK stabilization in colon cancer metastasis.
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KLHL39 appears to function as an antagonist that blocks ubiquitylation and degradation of PML and DAPK1 by KLHL20.
“the BTB-Kelch family member KLHL39 appears to function as an antagonist that blocks the ubiquitylation and degradation of PML and DAPK1 by KLHL20 (ref. 95 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [95]
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Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
- Authors
- Chen, H. Y., Hu, J. Y., Chen, T. H., Lin, Y. C., Liu, X., Lin, M. Y., Lang, Y. D., Yen, Y., & Chen, R. H.
- Affiliations
- Institute of Biological Chemistry, Academia Sinica (TW)
- National Taiwan University (TW)
- Taipei Medical University (TW)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Corresponding author
- Chen, R H
- Venue
- Oncogene
- Published
- 2015-01-26
- Volume
- 34
- Issue
- 40
- Pages
- 5141-5151
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2057911349
- Cited by
- 39
- References
- 40
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 5 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Academia Sinica
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- colon cancer metastasis, PML, DAPK, ubiquitination, protein stability, tumor suppressor proteins, cell migration and invasion, metastatic progression
- MeSH terms
- Promyelocytic Leukemia Protein, Animals, Carrier Proteins, Colonic Neoplasms, Female, Humans, Immunohistochemistry, Mice, Nude, Neoplasm Invasiveness, Neoplasm Metastasis, Nuclear Proteins, Transcription Factors, Transfection, RNA-Binding Proteins, Tumor Suppressor Proteins, RNA Interference, Cell Line, Tumor, Tissue Array Analysis, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice, Ubiquitination, Death-Associated Protein Kinases, Heterografts
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