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

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 in CRC. We demonstrate that USP17 directly interacts with and deubiquitinates β-catenin, preventing its degradation and enhancing its stability. CRISPR/Cas9-mediated knockout 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Bonneil

LAB HEAD: Marc Servant

PROVIDER: PXD065117 | Pride | 2026-02-25

REPOSITORIES: Pride

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			Action	DRS
	Service_Servant_2906_310124_1.mzid	Mzid
	Service_Servant_2906_310124_1a.mgf	Mgf
	Service_Servant_2906_310124_1a.raw	Raw
	Service_Servant_2906_310124_1b.mgf	Mgf
	Service_Servant_2906_310124_1b.raw	Raw

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Project description:Purpose: WNT signaling activation in colorectal cancers (CRCs) occurs mainly through APC inactivation or, more uncommonly, β-catenin activation. Both processes promote β-catenin nuclear accumulation, which transcriptionally up-regulates epithelial-to-mesenchymal transition (EMT)-related genes. Experimental Design: We investigated β-catenin localization, downstream gene expression, and phenotypic alterations in HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin localization and associated phenotypes in CRC tissues. Results: Wild-type β-catenin mainly localized at the cell membrane, whereas mutant showed predominantly nuclear localization; membranous, cytoplasmic, and nuclear localization was observed in HCT116-P cells. Microarray analysis revealed significant down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT cells. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT cells, although E-cadherin expression was unaffected. Altered expression of cell-cell junction-related molecules led to tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased migration and invasion activities of HCT116-WT, whereas AJ loss was required to further up-regulate these activities in HCT116-P. Immunohistochemistry analysis of 101 stage III CRC tissues revealed high nuclear β-catenin expression (≥30% of tumor cells) in 15 (14.9%) samples, low nuclear expression (1-29%) in 53 (52.5%) samples, and undetectable nuclear expression in 33 (32.6%) samples, with a trend toward more frequent down-regulation of Claudin-7 and E-cadherin, and increased metastasis in CRCs with high vs. low nuclear β-catenin. Conclusions: β-catenin activation and nuclear translocation induce EMT progression by modifying cell-cell junctions, and are associated with aggressive behaviors of CRCs.

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

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