Abstract 5215: EZH2-mediated STAT3 activation in glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor despite maximal therapy. Recent studies suggest that GBMs contain highly tumorigenic, stem cell-like cells termed glioblastoma stem cells (GSCs). GSCs significantly contribute to tumor propagation and treatment resistance and thus are critical target for curative therapy in GBMs. These GSCs share a key characteristic of normal stem cells, such as unlimited self-renewal capacity. Maintenance of the stem cell status in normal stem cells is governed by the Polycomb Repressive Complex 2 (PRC2)-mediated transcriptional repression. Enhancer of zeste homolog 2 (EZH2) is the only catalytically active component in PRC2, and it methylates a specific lysine residue of histone 3, resulting in the repressive chromatin structure. Signal transducer and activator of transcription 3 (STAT3) regulates diverse cellular processes and is frequently activated during tumorigenesis. Components of PRC2 are highly expressed in various cancers including GBMs and STAT3 is required for GSCs maintenance. In this study, we investigated the functional interaction between these two oncogenic pathways regulating GSCs phenotype. We show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor called 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA) inhibits STAT3 activity. Furthermore, AKT-mediated EZH2 phosphorylation affects STAT3 activity through STAT3 methylation. We demonstrate that STAT3 bind to EZH2 promoter and inhibition of STAT3 activity by small molecule inhibitor decrease PRC2 protein expression. Targeting of EZH2 and STAT3 by combined treatment with DZNep and STAT3 inhibitor strongly impairs GSCs self-renewal in vitro and decreases markers of neural stem cell multipotency. In addition, shEZH2 transduction + STAT3 inhibitor treatment extend survival of SCID mice with intracranial GSCs than shEZH2 single transduced group. Together, these obtained results strongly suggest the presence of positive feedback activation loop between PRC2 and STAT3 signaling in GSCs and targeting of this activation loop may offer an attractive therapeutic strategy for GBM. 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 5215. doi:1538-7445.AM2012-5215