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

• Published in: Nature communications Vol. 12; no. 1; pp. 2148 - 16
• Main Authors: Badodi, Sara, Pomella, Nicola, Zhang, Xinyu, Rosser, Gabriel, Whittingham, John, Niklison-Chirou, Maria Victoria, Lim, Yau Mun, Brandner, Sebastian, Morrison, Gillian, Pollard, Steven M., Bennett, Christopher D., Clifford, Steven C., Peet, Andrew, Basson, M. Albert, Marino, Silvia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 14/63; 38; 45; 45/91; 631/67/1922; 631/67/2327; 64/60; 82/80; 96/106; 96/95; Adaptation; Adaptation, Physiological - drug effects; Animals; Brain cancer; Brain tumors; Cell Count; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cerebellar Neoplasms - genetics; Chemotherapy; Chromatin remodeling; Cisplatin; Cisplatin - pharmacology; Cytotoxicity; Deregulation; DNA-Binding Proteins - metabolism; Drug Synergism; Epigenesis, Genetic - drug effects; Epigenetics; Humanities and Social Sciences; Humans; Inositol; Inositol - pharmacology; Medulloblastoma; Medulloblastoma - genetics; Metabolic rate; Metabolism; Mice; multidisciplinary; Neural Stem Cells - metabolism; Oxygen Consumption - drug effects; Pathogenesis; Phosphatidylinositols - metabolism; Polycomb Repressive Complex 1 - metabolism; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; Subgroups; T-Box Domain Proteins; TOR protein; TOR Serine-Threonine Kinases - metabolism; Toxicity; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22379-7

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. BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1 High /CHD7 Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.