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

Novellasdemunt, Laura; Foglizzo, Valentina; Cuadrado, Laura; Antas, Pedro; Kucharská, Anna; Encheva, Vesela; Snijders, Ambrosius P.; Li, Vivian

doi:10.1016/j.celrep.2017.09.072

Cited by 121 publications

(146 citation statements)

References 46 publications

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“…We only observed a reduction in IL‐1β cleavage and release in both ELISAs and Western blots when both DUBs were absent, and observed a similar phenotype with regard to caspase‐1 activation and pyroptosis. This is not the first time that functional redundancy has been suggested to exist between USP7 and USP47, and has already been implicated in the Wnt signalling pathway . Further studies will be needed to examine the exact targets of deubiquitination for these DUBs in this setting, to be able to assess such redundancy.…”

Section: Discussionmentioning

confidence: 92%

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

et al. 2018

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The assembly and activation of the inflammasomes are tightly regulated by post‐translational modifications, including ubiquitin. Deubiquitinases (DUBs) counteract the addition of ubiquitin and are essential regulators of immune signalling pathways, including those acting on the inflammasome. How DUBs control the assembly and activation of inflammasomes is unclear. Here, we show that the DUBs USP7 and USP47 regulate inflammasome activation in macrophages. Chemical inhibition of USP7 and USP47 blocks inflammasome formation, independently of transcription, by preventing ASC oligomerisation and speck formation. We also provide evidence that the ubiquitination status of NLRP3 itself is altered by inhibition of USP7 and USP47. Interestingly, we found that the activity of USP7 and USP47 increased in response to inflammasome activators. Using CRISPR/Cas9 in the macrophage cell line THP‐1, we show that inflammasome activation is reduced when both USP7 and USP47 are knocked down. Altogether, these data reveal a new post‐transcriptional role for USP47 and USP7 in inflammation by regulating inflammasome activation and the release of the pro‐inflammatory cytokines IL‐1β and IL‐18, and implicate dual USP7 and USP47 inhibitors as potential therapeutic agents for inflammatory disease.

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Section: Discussionmentioning

confidence: 92%

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

et al. 2018

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“…Surprisingly, NEDD4 and NEDD4L were still able to suppress Wnt activity in the absence of DVL2 (Fig 5D), suggesting that there might be additional player for NEDD4/4L-mediated Wnt inhibition. (Novellasdemunt et al, 2017) and DLD1 (APC-mutated CRC cells at 1,417a.a.) Similar to HEK293T cells, expression of NEDD4 and NEDD4L in the CRC cell line HCT116 strongly suppressed Wnt pathway activation (Fig 5E).…”

Section: Of 15mentioning

confidence: 99%

“…Immunohistochemistry was performed as described (Novellasdemunt et al, 2017). For small intestinal tissues, same proximal part of the small intestine from all genotypes was used throughout the study.…”

Section: Immunohistochemistry and Edu Stainingmentioning

confidence: 99%

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NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor

et al. 2019

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The intestinal stem cell (ISC) marker LGR5 is a receptor for Rspondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self-renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in homeostasis, regeneration and cancer, little is known about the post-translational regulation of LGR5. Here, we show that the HECT-domain E3 ligases NEDD4 and NEDD4L are expressed in the crypt stem cell regions and regulate ISC priming by degrading LGR receptors. Loss of Nedd4 and Nedd4l enhances ISC proliferation, increases sensitivity to RSPO stimulation and accelerates tumour development in Apc min mice with increased numbers of high-grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/bcatenin signalling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation. Our findings unveil the previously unreported post-translational control of LGR receptors via NEDD4/NEDD4L to regulate ISC priming. Inactivation of NEDD4 and NEDD4L increases Wnt activation and ISC numbers, which subsequently enhances tumour predisposition and progression.

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“…Up to the present, studies using CRISPR/Cas9 in relation to tumor development and research into treatment involving tumor suppressor genes have yielded some positive results. The main anti‐tumor research results of tumor suppressor genes are listed in Table (Part A‐D) …”

Section: Using Crispr/cas9 In the Study Of Tumor Therapiesmentioning

confidence: 99%

Application of CRISPR/Cas9 gene editing technique in the study of cancer treatment

et al. 2019

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In recent years, gene editing, especially that using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9, has made great progress in the field of gene function. Rapid development of gene editing techniques has contributed to their significance in the field of medicine. Because the CRISPR/Cas9 gene editing tool is not only powerful but also has features such as strong specificity and high efficiency, itcan accurately and rapidly screen the whole genome, facilitating the administration of gene therapy for specific diseases. In the field of tumor research, CRISPR/Cas9 can be used to edit genomes to explore the mechanisms of tumor occurrence, development, and metastasis. In these years, this system has been increasingly applied in tumor treatment research. CRISPR/Cas9 can be used to treat tumors by repairing mutations or knocking out specific genes. To date, numerous preliminary studies have been conducted on tumor treatment in related fields. CRISPR/Cas9 holds great promise for gene-level tumor treatment. Personalized and targeted therapy based on CRISPR/Cas9 will possibly shape the development of tumor therapy in the future. In this study, we review the findings of CRISPR/Cas9 for tumor treatment research to provide references for related future studies on the pathogenesis and clinical treatment of tumors.

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

Cited by 121 publications

References 46 publications

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor

Application of CRISPR/Cas9 gene editing technique in the study of cancer treatment

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