USP7 is a tumor-specific WNT activator for APC-mutated colorectal cancer by mediating β-catenin deubiquitination
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Laura Novellasdemunt Valentina Foglizzo Laura Cuadrado Pedro Antas Ania Kucharska Vesela Encheva Bram Snijders Vivian LiAbstract
The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRCs), resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation, and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations; thus, it can be used as a tumor-specific therapeutic target for most CRCs.
Journal details
Journal Cell Reports
Volume 21
Issue number 3
Pages 612-627
Available online
Publication date
Full text links
Publisher website (DOI) 10.1016/j.celrep.2017.09.072
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Europe PubMed Central 29045831
Pubmed 29045831