| Autor: |
Michaela Reissland, Oliver Hartmann, Saskia Tauch, Cristian Prieto-Garcia, Clemens Schulte, Daniel Solvie, Sinah Loebbert, Anne-Claire Jacomin, Marina Pesic, Jeroen Bugter, Christina Schülein-Völk, Carmina Fuss, Nikolett Pahor, Carsten Ade, Viktoria Buck, Michael Potente, Vivian Li, Gerti Beliu, Armin Wiegering, Eliya Bitman-Lotan, Tom Grossmann, Mathias Rosenfeldt, Martin Eilers, Hans Maric, Madelon Maurice, Florian Greten, Ivan Dikic, Amir Oryan, Peter Gallant, Markus Diefenbacher |
| Rok vydání: |
2023 |
| Popis: |
The contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of β-Catenin stability, potentiating WNT signalling and cancer stem cells and CRC. Mechanistically, interaction and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Reduction of USP10 induces the expression of differentiation genes and opposes the APC-truncated phenotype in an intestinal hyperplasia model. Notably, loss of USP10 in CRISPR engineered intestinal organoids opposed the super competitor-signalling and reduced tumorigenic properties of APC-mutated CRC. Taken together, our findings reveal USP10s role in CRC cell identity, stemness and tumour growth by stabilising β-Catenin, leading to aberrant WNT signalling, and implicate USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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