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

被引：134

作者：

Novellasdemunt, Laura ^{[1
]}

Foglizzo, Valentina ^{[1
]}

Cuadrado, Laura ^{[1
]}

Antas, Pedro ^{[1
]}

Kucharska, Anna ^{[1
]}

Encheva, Vesela ^{[2
]}

Snijders, Ambrosius P. ^{[2
]}

Li, Vivian S. W. ^{[1
]}

机构：

[1] Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England

[2] Francis Crick Inst, Mass Spectrometry Sci Technol Platform, 1 Midland Rd, London NW1 1AT, England

来源：

CELL REPORTS | 2017年 / 21卷 / 03期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

FAMILIAL ADENOMATOUS POLYPOSIS; UBIQUITIN LIGASE; STEM-CELLS; COLI GENE; E3; LIGASE; MUTATIONS; DEGRADATION; PATHWAY; IDENTIFICATION; COMPLEX;

D O I：

10.1016/j.celrep.2017.09.072

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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

引用

页码：612 / 627

页数：16

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