USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.

Journal

Oncogene

ISSN: 1476-5594

Titre abrégé: Oncogene

Pays: England

ID NLM: 8711562

Informations de publication

Date de publication:
23 Oct 2024

Historique:

received: 12 12 2023

accepted: 21 08 2024

revised: 30 07 2024

medline: 24 10 2024

pubmed: 24 10 2024

entrez: 24 10 2024

Statut: aheadofprint

Résumé

The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC.

Identifiants

DOI: 10.1038/s41388-024-03141-x PMID: 39443725

pubmed: 39443725

doi: 10.1038/s41388-024-03141-x

pii: 10.1038/s41388-024-03141-x

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

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