期刊
CELL REPORTS
卷 21, 期 3, 页码 612-627出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.072
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资金
- Francis Crick Institute from Cancer Research UK [FC001105]
- UK Medical Research Council [FC001105]
- Wellcome Trust [FC001105]
- Medical Research Council [MC_UP_1202/7, 1363171] Funding Source: researchfish
- The Francis Crick Institute [668294 - INTENS, 10105, 10011] Funding Source: researchfish
- MRC [MC_UP_1202/7] Funding Source: UKRI
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.
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