USP7 Is a Tumor-Specific WNT Activator for APC-Mutated Colorectal Cancer by Mediating β-Catenin Deubiquitination

• Main Authors: Laura Novellasdemunt, Valentina Foglizzo, Laura Cuadrado, Pedro Antas, Anna Kucharska, Vesela Encheva, Ambrosius P. Snijders, Vivian S.W. Li
• Format: Article
• Language: English
• Published: Elsevier 2017-10-01
• Series: Cell Reports
• Subjects: Wnt signaling; APC; β-catenin; ubiquitination; USP7; colorectal cancer
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124717313773

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.