USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer
Open accessPublished version of a preprint
Abstract
The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
USP10 Regulates p53 Localization and Stability by Deubiquitinating p53
Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010) · Cell · doi:10.1016/j.cell.2009.12.032 · Cited by 637 · cited 1× · see citing works
“USP10 was reported to control the protein stability of TP53 [46, 47] and contribute to control of autophagy [48, 49], DNA damage [50, 51] and metabolic signalling [51, 52], all processes that tumour cells highly rely on [53].”
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
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- Authors
- Reissland, M., Hartmann, O., Tauch, S., Bugter, J. M., Prieto-Garcia, C., Schulte, C., Loebbert, S., Solvie, D., Bitman-Lotan, E., Narain, A., Jacomin, A.-C., Schuelein-Voelk, C., Fuss, C. T., Pahor, N., Ade, C., Buck, V., Potente, M., Li, V., Beliu, G., Wiegering, A., Grossmann, T., Eilers, M., Wolf, E., Maric, H., Rosenfeldt, M., Maurice, M. M., Dikic, I., Gallant, P., Orian, A., & Diefenbacher, M. E.
- Affiliations
- University of Würzburg (DE)
- German Cancer Research Center (DE)
- University Medical Center Utrecht (NL)
- Technion – Israel Institute of Technology (IL)
- Goethe University Frankfurt (DE)
- Max Delbrück Center (DE)
- The Francis Crick Institute (GB)
- Corresponding author
- Diefenbacher, Markus E.
- ORCID
- Reissland, Michaela
- Tauch, Saskia
- Bugter, Jeroen M.
- Schulte, Clemens
- Solvie, Daniel
- Bitman-Lotan, Eliya
- Narain, Ashwin
- Jacomin, Anne-Claire
- Fuss, Carmina T.
- Ade, Carsten
- Buck, Viktoria
- Potente, Michael
- Li, Vivian
- Beliu, Gerti
- Wiegering, Armin
- Grossmann, Tom
- Eilers, Martin
- Wolf, Elmar
- Maric, Hans
- Rosenfeldt, Mathias
- Maurice, Madelon M.
- Dikic, Ivan
- Gallant, Peter
- Orian, Amir
- Diefenbacher, Markus E.
- Venue
- Oncogene
- Published
- 2024-10-23
- Volume
- 43
- Issue
- 50
- Pages
- 3645-3659
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC11611742
- OpenAlex
- W4403684125
- Cited by
- 16
- References
- 4
- Citations by year
- 2026: 6 · 2025: 10
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-01-22)
- Open access
- hybrid
- doi.org
- Locations
- Oncogene (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Funders
- Israel Cancer Research Fund
- Francis Crick Institute (CC2141)
- Deutsche Forschungsgemeinschaft (GRK 2243, MA 6957/1-1, INST 93/1023-1-FUGG, 440766788)
- Deutsche Krebshilfe (#70112951, 70112491, 70114554)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- USP10, deubiquitinase, β-catenin stabilization, colorectal cancer, cancer stemness, Wnt signaling, tumor organoids, tumorigenicity, protein degradation, therapeutic target
- MeSH terms
- Animals, Esterases, Humans, Neoplastic Stem Cells, Colorectal Neoplasms, Signal Transduction, Adenomatous Polyposis Coli Protein, Ubiquitin Thiolesterase, Cell Line, Tumor, beta Catenin, Mice, Wnt Signaling Pathway
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