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

Autor:	Reissland M; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany.; Max Planck Institute for Molecular Genetics, Berlin, Germany., Hartmann O; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany., Tauch S; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.; Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany., Bugter JM; Oncode Institute and Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands., Prieto-Garcia C; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.; Molecular Signalling Group, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt am Main, Germany., Schulte C; Rudolf-Virchow-Center for Integrative and Translational Imaging, University of Wuerzburg, Wuerzburg, Germany., Loebbert S; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany.; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany., Solvie D; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany., Bitman-Lotan E; Faculty of Medicine, TICC, Technion Haifa, Haifa, Israel., Narain A; Cancer Systems Biology Group, University of Wuerzburg, Am Hubland, Wuerzburg, Germany., Jacomin AC; Molecular Signalling Group, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt am Main, Germany., Schuelein-Voelk C; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany., Fuss CT; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.; Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany., Pahor N; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany., Ade C; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany., Buck V; Institute for Pathology, University of Würzburg, Wuerzburg, Germany., Potente M; Angiogenesis & Metabolism Laboratory, Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin Germany and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Li V; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK., Beliu G; Institute of Lung Health and Immunity, Helmholtz Center, Munich, Germany., Wiegering A; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany.; Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, University Hospital, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany., Grossmann T; Amsterdam Institute of Molecular and Life Sciences, Amsterdam, Netherlands., Eilers M; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany.; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany., Wolf E; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany.; Cancer Systems Biology Group, University of Wuerzburg, Am Hubland, Wuerzburg, Germany., Maric H; Rudolf-Virchow-Center for Integrative and Translational Imaging, University of Wuerzburg, Wuerzburg, Germany., Rosenfeldt M; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany.; Institute for Pathology, University of Würzburg, Wuerzburg, Germany., Maurice MM; Oncode Institute and Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands., Dikic I; Molecular Signalling Group, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt am Main, Germany., Gallant P; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Wuerzburg, Germany., Orian A; Faculty of Medicine, TICC, Technion Haifa, Haifa, Israel., Diefenbacher ME; Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany. markus.diefenbacher@helmholtz-munich.de.; Mildred-Scheel Early Career Cancer Center, Wuerzburg, Germany. markus.diefenbacher@helmholtz-munich.de.; Institute of Lung Health and Immunity, Helmholtz Center, Munich, Germany. markus.diefenbacher@helmholtz-munich.de.; German Center for Lung Research, DZL, Germany. markus.diefenbacher@helmholtz-munich.de.; Ludwig Maximilian University Munich, Munich, Germany. markus.diefenbacher@helmholtz-munich.de.
Jazyk:	angličtina
Zdroj:	Oncogene [Oncogene] 2024 Dec; Vol. 43 (50), pp. 3645-3659. Date of Electronic Publication: 2024 Oct 23.
DOI:	10.1038/s41388-024-03141-x
Abstrakt:	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. Competing Interests: Competing interests: MED is associated editor at Oncogene. Consent for publication: We have obtained consent to publish this paper from all the study participants. (© 2024. The Author(s).)
Databáze:	MEDLINE
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