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

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.