Epigenetics in Brain Tumors: HDACs Take Center Stage

Abstract

Primary tumors of the brain account for 2 % of all cancers with malignant gliomas taking the lion's share with 70 %. Malignant gliomas (high grade gliomas WHO degrees III and degrees IV) belong to one of the most threatening tumor entities known with their disappointingly short median survival time of just 14 months despite maximum therapy according to current gold standards. Malignant gliomas secrete various factors, through which they adapt and manipulate the tumor microenvironment to their advantage. Epigenetic mechanisms operate on the tumor microenvironment by de- and methylation processes and imbalances between the histone deacetylases (HDAC) and histone acetylases (HAT). Many compounds have been discovered modulating epigenetically controlled signals. Recent studies indicate that xCT (system xc-, SLC7a11) and CD44 (H-CAM,ECM-III, HUTCH-1) functions as a bridge between these epigenetic regulatory mechanisms and the malignant glioma progression. The question that ensues is the extent to which therapeutic intervention on these signaling pathways would exert influence on the treatment of malignant gliomas as well as the extent to which manipulation of HDAC activity can sensitize tumor cells for chemotherapeutics through 'epigenetic priming'. Considering the current stagnation in the development of therapeutic options the need for new strategies in the treatment of gliomas has never been so urgent. Here, the possibility of pharmacological intervention on tumor-associated genes by epigenetic priming opens a novel path in combating primary brain tumors.