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Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156077 | GEO | 2021/03/04

REPOSITORIES: GEO

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Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (HumanMethylation850)

Project description:Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma (MB), 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 BMI1High;CHD7Low 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 BMI1High;CHD7Low xenograft model.

2021-03-04 | GSE155962 | GEO

Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (RNA-seq, ChIP-seq)

2021-03-04 | GSE154394 | GEO

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

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| S-EPMC8042111 | biostudies-literature

Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma

Project description:Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma

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Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (HumanMethylation850)

Project description:Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (HumanMethylation850)

| PRJNA656374 | ENA

Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (RNA-seq, ChIP-seq)

Project description:Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (RNA-seq, ChIP-seq)

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Epigenetic regulation in medulloblastoma.

Project description:Medulloblastoma is the most common malignant childhood brain tumor. The heterogeneous tumors are classified into four subgroups based on transcription profiles. Recent developments in genome-wide sequencing techniques have rapidly advanced the understanding of these tumors. The high percentages of somatic alterations of genes encoding chromatin regulators in all subgroups suggest that epigenetic deregulation is a major driver of medulloblastoma. In this report, we review the current understanding of epigenetic regulation in medulloblastoma with a focus on the functional studies of chromatin regulators in the initiation and progression of specific subgroups of medulloblastoma. We also discuss the potential usage of epigenetic inhibitors for medulloblastoma treatment.

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Brain regulation of emotional conflict predicts antidepressant treatment response for depression.

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Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules.

Project description:Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial-mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.

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