Abstract 3446: Inhibition of EZH2 suppresses medulloblastoma cell growth

Abstract

Abstract EZH2 (enhancer of zeste homologue2) is a polycomb group protein that mediates repression of gene transcription through its Histone 3 Lysine 27methyltransferase activity. EZH2 is highly expressed in many cancers including metastatic prostate cancer, breast cancer, and glioblastoma multiform. EZH2 expression is associated with tumor cell proliferation, invasive growth and aggressive cancer phenotypes. The fact that EZH2 increases tumor cell proliferation and aggressive subgroups in several cancers may be of practical interest because the polycomb proteins have been suggested as candidates for targeted therapy. We found EZH2 expression to be increased in medulloblastoma when compared to normal cerebellum. Inhibition of EZH2 by RNAi in medulloblastoma cells resulted in suppression of cell growth. To further examine this phenotype we used a global histone methylation inhibitor, 3-Deazaneplanocin A (DZNep). DZNep preferentially inhibits H3 Lys27me via EZH2. DZNep showed a dose dependent, anti-proliferative and anti-clonogenic activity in medulloblastoma cells. Synergetic effect was shown in cells transfected with shEZH2 and treated with DZNEP. Furthermore DZNep treatment decreased EZH2 protein levels. We found that DZNep induced differentiation of mouse neural stem cells even when they are grown in proliferation medium. Most critically transformation of these neural stem cells was significantly attenuated by shEZH2 and DZNep. Our results suggest that EZH2 is a target for medulloblastoma treatment and that DZNep is an excellent candidate for further testing as a therapeutic candidate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3446. doi:10.1158/1538-7445.AM2011-3446