Abstract

Aberrant Wnt signalling has been associated with many types of cancer and other diseases, and is therefore an attractive target for therapeutic intervention. Thus far, no approved drugs are available in the clinic for treatment of Wnt signalling pathway despite the substantial effort put on therapeutic development of Wnt inhibitors in the past two decades. One major challenge of drugging the Wnt pathway is due to its crucial role in normal development and adult tissue homeostasis. We aim to identify novel therapeutic targets in Wnt signalling for cancer treatment. The tumour 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 tumour 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 tumour growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations, thus can be used as tumour-specific therapeutic target for most CRCs.