Abstract 3135: Epigenetic regulation of miR-1275 through histone H3 lysine 27 trimethylation during human glioma stem-like cell differentiation

Abstract

Abstract Functional and morphological heterogeneity characterizes aggressive glioblastoma and contributes to invasion, metastasis and drug resistance. The molecular mechanisms underlying this heterogeneity are poorly understood. Recent studies have revealed that tumors contain a minor population of tumor-initiating cells, called cancer stem cells (CSCs). The CSCs are considered able to aberrantly differentiate into diverse cell types. Such stem-like cancer cells have been well characterized in glioblastoma multiforme, and are referred to as glioma stem-like cells (GSCs). Using GSCs as a model, we investigated the roles of micro-RNA (miR) in GSCs differentiation. miR-microarray showed that 19 and 48 miRs were commonly upregulated and downregulated in two GSC lines during the differentiation, respectively. Among those miRs, quantitative-PCR analysis showed that miR-1275 was consistently downregulated during the GSC differentiation, while the expression of its target, oligodendrocyte specific protein (OSP/CLDN11), a marker of oligodendrocyte, was upregulated. Compellingly, inhibition of miR-1275 using specific antisense oligonucleotide increased the expression of OSP in GSC. Epigenetic analysis revealed that level of histone H3 lysine 27 trimethylation(H3K27me3) was enriched in the promoter of pri-miR-1275 during the GSC differentiation. Treatment of 3-Dezaneplanocin-A, an inhibitor of H3K27me3, impaired the GSC differentiation in parallel with sustained miR-1275 expression. In general, astrocytic component is the most prevalent in glioblastomas, while a subset of cases also contain an oligodendroglial component in the tumors. Our results illuminated the epigenetic regulatory pathways of miR-1275 closely associated with oligodendroglial differentiation, which may contribute to the tissue heterogeneity formation of glioblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3135. doi:1538-7445.AM2012-3135