Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Autor: Badodi S; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Pomella N; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Zhang X; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Rosser G; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Whittingham J; Centre for Craniofacial and Regenerative Biology, King's College London, London, UK., Niklison-Chirou MV; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath, UK., Lim YM; UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK., Brandner S; UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK., Morrison G; Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK., Pollard SM; Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK., Bennett CD; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.; Birmingham Women and Children's Hospital, Birmingham, UK., Clifford SC; Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle upon Tyne, UK., Peet A; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.; Birmingham Women and Children's Hospital, Birmingham, UK., Basson MA; Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK., Marino S; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. s.marino@qmul.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Apr 12; Vol. 12 (1), pp. 2148. Date of Electronic Publication: 2021 Apr 12.
DOI: 10.1038/s41467-021-22379-7
Abstrakt: Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1 High ;CHD7 Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1 High ;CHD7 Low xenograft model.
Databáze: MEDLINE
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