The ketogenic diet alters the epigenetic landscape of GBM to potentiate the effects of chemotherapy and radiotherapy

Abstract

Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumour, with a median survival of 12–14 months after diagnosis. Although GBM has been extensively characterised on the molecular level during the past decades, many targeted therapies have been proved to be ineffective due to high heterogeneity of GBM. Thus, novel therapies targeting the altered metabolism which is exhibited by all cancer cells have gained more attentions. Our strategy is the therapeutic ketogenic diet (KD), a high fat, low carbohydrate and adequate protein diet, which has been recognized as a treatment for refractory paediatric epilepsy. Recent studies have shown that KD reduces tumour growth and potentiates the effects of radiotherapy in some glioma animal models. However, the underlying mechanism is still unclear. To unravel the mechanism of action, we carried out small-RNA sequencing and chromatin modifying enzyme analysis using brain tumour samples from GBM mice model, fed with either KD or standard diet (SD). Our results highlighted an overall upregulation of tumour suppressor miRNAs and key chromatin modifying enzymes that are typically downregulated in GBM in mice fed with KD compared with those fed with SD. We also observed a corresponding downregulation in target genes of these miRNAs and chromatin modifying enzymes. These genes have been reported as key regulators in tumour growth, tumour invasion and chemo/radio-resistance in previous publications. Therefore, our study indicates that targeting cancer metabolism using the KD alters the epigenetic landscape of GBM and induces changes in key genes that potentiate the effects of chemo/radiotherapy.