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

ABSTRACT: 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 ?-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes ?-catenin deubiquitination through reverse binding of ?-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring ?-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.

SUBMITTER: Novellasdemunt L 

PROVIDER: S-EPMC5656747 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature