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The deubiquitinase USP17 regulates the expression and activity of the oncogenic driver β-catenin in colorectal cancer

Oncogene volume 45, pages 989–998 (2026)Cite this article

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Abstract

Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer (CRC). Here, we identify the deubiquitinating enzyme USP17 as a critical regulator of β-catenin stability and activity in CRC. We demonstrate that USP17 directly interacts with and deubiquitinates β-catenin, preventing its degradation and enhancing its stability. CRISPR/Cas9-mediated knockdown of USP17 in CRC-derived cell lines significantly reduced β-catenin levels and suppressed epithelial-mesenchymal transition (EMT), as evidenced by distinct morphological changes and altered expression of classical EMT markers. USP17 depletion reduced the proliferation of CRC cell lines and impaired CRC tumor growth in vivo. Conversely, USP17 overexpression in immortalized rat enterocytes elevated β-catenin levels and enhanced KRAS-induced cell proliferation. RNA sequencing and quantitative proteomic analysis of USP17-depleted CRC cells revealed significant suppression of the transcriptional coactivator function of β-catenin, impacting key oncogenic-related pathways. Our findings establish USP17 as a key regulator of β-catenin signaling and highlight its potential as a candidate therapeutic target in CRC.

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Fig. 1: USP17 regulates β-catenin protein stability.
Fig. 2: USP17 stabilizes cytoplasmic β-catenin by direct deubiquitination.
Fig. 3: USP17 expression correlates with CRC cell proliferation and tumorigenesis.
Fig. 4: Transcriptomic and proteomic analyses reveal attenuated β-catenin signaling and mitogenic signatures upon depletion of USP17 in CRC cells.

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Data availability

The data supporting this study’s findings are available from the corresponding author upon reasonable request. The RNA sequencing (RNA-Seq) data generated in this study have been deposited in NCBI GEO (GSE298365). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [58] partner repository with the dataset identifier PXD065117 and 10.6019/PXD065117.

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Acknowledgements

This work was supported by a Cancer Research Society (CRS) grant to MJS and a Canadian Institutes for Health Research (CIHR) Grant to MJS and SM.

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Author notes

  1. These authors contributed equally: Mariana Acevedo, Florence Dô, Firas El-Mortada.

Authors and Affiliations

  1. Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada

    Mariana Acevedo, Florence Dô, Firas El-Mortada & Marc J. Servant

  2. Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada

    Florence Dô, Laure Voisin, Thibault Houles, Geneviève Lavoie, Philippe P. Roux, Eric Bonneil & Sylvain Meloche

  3. Gilead Science Canada, Mississauga, ON, Canada

    Pierre-Luc Tanguay

  4. Goodman Cancer Institute, Montréal, QC, Canada

    David Allard, John Stagg, Samuel Doré & Logan Walsh

  5. Faculty of Medicine, Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada

    David Allard & John Stagg

  6. Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Philippe P. Roux

  7. Human Genetics Department, McGill University, Montréal, QC, Canada

    Samuel Doré & Logan Walsh

  8. Sygnature Discovery, Saint-Laurent, QC, Canada

    Jimmy Fourtounis

  9. Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Sylvain Meloche

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  1. Mariana Acevedo
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Contributions

Conceived and designed the experiments: MJS, SM, MA, FD, PLT, LV, JS. Performed the experiments: MA, FD, FEM, PLT, LV, GL, DA, JF, EB. Analyzed the data: MJS, SM, MA, FEM, PLT, LV, TH, GL, DA, PPR, JS, SD, LW, EB. Contributed reagents/materials/analysis tools: PPR, JS, LW, EB. Wrote the first draft manuscript: MJS. Edited the manuscript: MJS, SM, MA, FD, FEM, JS, PPR, SD, EB.

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Correspondence to Sylvain Meloche or Marc J. Servant.

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Acevedo, M., Dô, F., El-Mortada, F. et al. The deubiquitinase USP17 regulates the expression and activity of the oncogenic driver β-catenin in colorectal cancer. Oncogene 45, 989–998 (2026). https://doi.org/10.1038/s41388-026-03695-y

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