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This study explores the role of FBXO6, a ubiquitination-related protein, in regulating CRC malignancy, particularly cell migration and invasion. Our analysis reveals that higher FBXO6 expression correlates with better prognosis in CRC patients, although its expression decreases in advanced-stage tumors. Functional studies demonstrate that FBXO6 overexpression suppresses the invasive and migratory abilities of HCT116 and RKO cells and reduces single-cell colony formation. In contrast, FBXO6 knockdown promotes these malignant traits. Immunoprecipitation and mass spectrometry analyses identified ITGB1 as a key substrate of FBXO6, with potential prognostic relevance in CRC. Subsequent in vitro assays confirmed this interaction, revealing that FBXO6 binds ITGB1 at its glycoprotein recognition site, thereby reducing ITGB1 stability and attenuating downstream FAK\/PI3K\/AKT\/ERK signaling. ITGB1 overexpression counteracts the suppressive effects of FBXO6, restoring downstream signaling activity. In vivo xenograft models further validate these findings: FBXO6 overexpression reduces tumor growth, Ki67 levels, and ITGB1-associated signaling. Additional rescue experiments show that FBXO6 counteracts the tumor-promoting effects of ITGB1 overexpression. In conclusion, FBXO6 suppresses CRC cell proliferation, migration, and invasion by targeting ITGB1 for ubiquitination and disrupting key oncogenic signaling pathways, thereby supporting its potential as a prognostic biomarker and candidate therapeutic target in CRC.<\/jats:p>","DOI":"10.1038\/s41419-026-08554-y","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T20:52:11Z","timestamp":1773953531000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FBXO6 regulates colon cancer migration and invasion via ITGB1 ubiquitination and downstream signaling"],"prefix":"10.1038","volume":"17","author":[{"given":"Niansheng","family":"Ren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxu","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuekun","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1186-4336","authenticated-orcid":false,"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"8554_CR1","doi-asserted-by":"crossref","unstructured":"Lichtenstern CR, Ngu RK, Shalapour S, Karin M. 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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from individual participants. Ethical approval for the human participants was obtained from the Ethics Committee of The First Affiliated Hospital of Harbin Medical University under license number (NO. 2022184). Ethical approval for the animal experiment was obtained from the Ethics Committee of The First Affiliated Hospital of Harbin Medical University under license number (NO. 2022156).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"324"}}