Dataset Information

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

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

SUBMITTER: Novellasdemunt L

PROVIDER: S-EPMC5656747 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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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]

PMID: 29045831

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Project description:Simple Summary Hyperactivation of the canonical Wnt and inactivation of the Hippo pathway are well-known genetic backgrounds for familial adenomatosis polyposis (FAP) and colorectal cancer (CRC), although the reciprocal regulation between those pathways is not yet clear. In this study, we found that Axin2, a bona fide downstream target of canonical Wnt, activates the Hippo pathway in APC-mutated CRC, limiting the therapeutic potential of niclosamide on advanced CRC through the inactivation of the Hippo pathway. To overcome the limitation, we combined niclosamide with AMPK activator metformin to activate Hippo and found that this combination synergistically suppressed canonical Wnt and activated Hippo in APC-mutated CRC. Using patient-derived cancer organoid and an APC-MIN mice model, we found the combinatory approach to be effective for APC-mutated CRC. Our results provide not only the reciprocal link between Wnt and Hippo in APC-mutated CRC, but they also provide an effective therapeutic approach with clinically available drugs for FAP and CRC patients. Abstract The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

Dataset Information

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

Publications

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

Similar Datasets

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