EPIG-10ABERRANT EPIGENOME IN GLIOBLASTOMA MULTIFORME

Abstract

The fact that epigenetic alterations collaborate with genetic mutations to drive the evolution of cancer towards malignancy prompted us to dissect the aberrant epigenome with focus on post-translational modifications in glioblastoma multiforme (GBM). We initially utilized qualitative and quantitative proteome by Tandem Mass Tagging Orbitrap-Elite spectrometry and identified differential histone modification patterns in four distinct types of MRI-characterized GBM compared to control brain regions. We found that trimethylation on histone 3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3), as well as acetylation on histone 3 lysine 9 (H3K9ac), lysine 27 (H3K27ac), and lysine 36 (H3K36ac) are altered in GBM. As these histone modifications are known to be either chromatin active or repressive marks, we carried out chromatin immunoprecipitation and deep-sequence (ChIP-Seq) to delineate differential enrichment of GBM genome by these histone modifications, and in parallel use RNA-Seq for gene expression profile of GBM. Through integrated analyses of ChIP-Seq and RNA-Seq, we found that changes in histone modification lead to very widespread effect on gene expression including cell cycle, cell death, mitochondrial metabolism, as well as PI3K and mTOR signaling pathways. Our studies highlight potential candidates for therapeutic targets of GBM. In addition, our proteomic analysis showed that neural stem and progenitor cell markers are highly expressed in GBM, suggesting that heterogeneous population of GBM share features with non-neoplastic stem cells. How changes in chromatin status could transform the normal stem cell toward cancer-initiating cells in GBM remain to be determined. Our future study will utilize single-cell RNA-Seq and proteome to thoroughly dissect the mechanism of cancerous initiation of GBM at single cell level. Emerging findings will diversify the approaches to cancer control and care by providing potential biomarkers for cancer diagnosis and prognosis.