EXTH-16. THE KETONE BODY β-HYDROXYBUTYRATE INHIBITS HISTONE DEACETYLASE ACTIVITY AND ALTERS EXPRESSION OF DNA REPAIR PROTEINS IN MALIGNANT GLIOMA CELLS

Abstract

Several preclinical studies support the use of the therapeutic ketogenic diet (KD) as an adjuvant therapy for malignant glioma. These studies have demonstrated that this approach alters multiple hallmarks of cancer growth, and it may also enhance other therapeutic modalities. We have demonstrated that the KD greatly increases survival in a mouse model of malignant glioma when administered ad libitum in combination with radiation, yet the underlying mechanisms have not been fully elucidated. The KD causes a decrease in blood glucose and an increase in the blood ketones acetoacetate and beta-hydroxybutyrate (betaHB). It was recently demonstrated that betaHB inhibits histone deacetylase (HDAC) activity in normal mouse tissue. Evidence suggests that many cancers exhibit increased HDAC activity which contributes to the epigenetic milieu found in tumors, alters DNA damage repair, and impacts radiosensitivity As the use of HDAC inhibitors for the treatment of brain tumors has generated great interest, we examined the effect of betaHB on HDAC activity and radiosensitivity in the context of malignant glioma. We now report that betaHB inhibits HDAC activity in a dose dependent manner in glioma cells and decreases expression of DNA damage repair proteins including RAD51, KU70, KU80, MRE11, and NBS1. We also found that betaHB radiosensitizes mouse glioma cells, cells from human glioblastomas and human glioma stem-like cells in vitro. Further, cell cycle analysis demonstrated that betaHB induces G2 arrest, providing an additional potential mechanism for the observed radiosensitivity. Western blot anal- yses show decreased expression of cyclin B1 and activation of cyclin-dependent kinase 2 (CDC2), two proteins that modulate G2 progression. Taken together this data opens up another avenue for understanding the mechanisms underlying the KD and its impact on radiation therapy, ultimately helping us better understand how to implement it for clinical use.