Abstract
SummaryThe 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.
Highlights
The canonical Wnt/b-catenin signaling pathway is evolutionarily conserved and plays crucial roles in many biological processes, such as stem cell maintenance and cell fate decision (Clevers and Nusse, 2012)
We have previously shown that adenomatous polyposis coli (APC) truncation activates Wnt/b-catenin signaling through abrogation of b-catenin ubiquitination within the destruction complex in colorectal cancers (CRCs), while assembly of the complex is not affected (Li et al, 2012)
We find that the deubiquitinating enzymes (DUBs) enzyme USP7 is crucial in sustaining pathological, but not physiological, Wnt activation in APC-truncated CRCs by mediating b-catenin deubiquitination
Summary
The canonical Wnt/b-catenin signaling pathway is evolutionarily conserved and plays crucial roles in many biological processes, such as stem cell maintenance and cell fate decision (Clevers and Nusse, 2012). The key downstream modulator of the pathway, b-catenin, is tightly regulated by phosphorylation and ubiquitination-mediated degradation in the cytoplasmic b-catenin destruction complex. Aberrant Wnt activation has been associated with many human cancer types, especially colorectal cancer (CRC) (Clevers and Nusse, 2012; MacDonald et al, 2009; Vogelstein and Kinzler, 2004). We have previously shown that APC truncation activates Wnt/b-catenin signaling through abrogation of b-catenin ubiquitination within the destruction complex in CRCs, while assembly of the complex is not affected (Li et al, 2012). Despite the crucial role of the CID in Wnt/b-catenin signaling regulation, little is known about the underlying mechanism. A more recent study proposed another speculative model: GSK3-mediated phosphorylation around the CID region promotes a conformational change in APC protein that allows the transfer of phospho-b-catenin to the E3 ligase (Pronobis et al, 2015)
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