Proteomics

Dataset Information

63

USP7 is a tumor-specific WNT activator for APC-mutated colorectal cancer by mediating B-catenin deu


ABSTRACT: The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRC) resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of 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 can be used as tumor-specific therapeutic target for most CRCs.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus musculus   Homo sapiens  

TISSUE(S): Tissue Not Applicable To Dataset

DISEASE(S): Not Available

SUBMITTER: Andrew Jones  

LAB HEAD: Bram Snijders

PROVIDER: PXD007947 | Pride | 2017-11-09

REPOSITORIES: Pride

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Publications

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

Novellasdemunt Laura L   Foglizzo Valentina V   Cuadrado Laura L   Antas Pedro P   Kucharska Anna A   Encheva Vesela V   Snijders Ambrosius P AP   Li Vivian S W VSW  

Cell reports 20171001 3


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  ...[more]

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