Epigenetic Targeting of Glioblastoma

Abstract

Glioblastoma is one of the first tumors where the biological changes accompanying a single epigenetic modification, the methylation of the MGMT gene, were found to be of clinical relevance. The exploration of the epigenomic landscape of glioblastoma has allowed to identify patients carrying a diffuse hypermethylation at gene promoters and with better outcome. Epigenetic and genetic data have led to the definition of major subgroups of glioma and were the basis of the current WHO classification of CNS tumors and of a novel classification based solely on DNA methylation data that shows a remarkable diagnostic precision.The reversibility of epigenetic modifications is considered a therapeutic opportunity in many tumors also because these alterations have been mechanistically linked to the biological characteristics of glioblastoma. Several alterations like IDH1/2 mutations that interfere with "epigenetic modifier" enzymes, the mutations of the histone 3 variants H3.1 and H3.3 that alter the global H3K27me3 levels and the altered expression of histone methyltransferases and demethylases are considered potentially druggable targets in glioma and molecules targeting these alterations are being tested in preclinical and clinical trials. The recent advances on the knowledge of the players of the "epigenetic orchestra" and of their mutual interactions are indicating new paths that may eventually open new therapeutic options for this invariably lethal cancer.

Keywords: DNA methylation; epigenetics; glioblastoma; histone code; therapy.

Figure 1

Schematic representation of the interplay between the different epigenetic layers. ncRNA can directly influence genome activity by interfering with transcripts or, indirectly, by degrading transcripts involved in DNA methylation, histone modification or chromatin remodeling. On the other hand ncRNA can be epigenetically inactivated by DNA methylation (11, 12). DNA methylation can directly interfere with gene expression and, indirectly, can regulate the expression of chromatin and histone modifiers.

Figure 2

Schematic representation of the different subtypes of glioma with the principal molecular and epigenetic characteristics. In this chart are represented the possible carcinogenic evolutions of the precursor cells. The major genetic and epigenetic alterations are reported along with the clinical characteristics of each subtype.