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

Publication date: 17 October 2017
Source:Cell Reports, Volume 21, Issue 3
Author(s): Laura Novellasdemunt, Valentina Foglizzo, Laura Cuadrado, Pedro Antas, Anna Kucharska, Vesela Encheva, Ambrosius P. Snijders, Vivian S.W. Li
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.

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Teaser

Novellasdemunt et al. find that an APC-truncating mutation activates Wnt signaling by promoting USP7-mediated β-catenin deubiquitination. USP7 inhibition significantly suppresses tumor growth of APC-mutated colon cancer cells but does not affect cells with wild-type APC, suggesting that it can be used as a tumor-specific drug target.


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