USP7 is a tumor-specific WNT activator for APC-mutated colorectal cancer by mediating β-catenin deubiquitination
journal contributionposted on 15.10.2020, 09:52 authored by Laura Novellasdemunt, Valentina Foglizzo, Laura Cuadrado, Pedro Antas, Anna Kucharska, Vesela Encheva, Ambrosius P Snijders, Vivian SW 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.
APCUSP7Wnt signalingcolorectal cancerubiquitinationβ-cateninAdenomatous Polyposis Coli ProteinAmino Acid SequenceAnimalsCell DifferentiationCell Line, TumorCell ProliferationColorectal NeoplasmsHEK293 CellsHumansMiceMutationOrganoidsProtein BindingProtein DomainsSmall Molecule LibrariesUbiquitin-Specific Peptidase 7UbiquitinationWnt Signaling Pathwaybeta Cateninbeta-Transducin Repeat-Containing ProteinsPRTPC-ackBRF-ackHP-ackLi, V FC0011050601 Biochemistry and Cell Biology