PolycombGroup Protein Enhancer of Zeste 2 Is an Oncogene That Promotes the Neoplastic Transformation of a

Polycomb group protein enhancer of zeste 2 (EZH2) is a master regulatory protein that plays a critical role in development as part of the polycomb repressive complex 2. Polycomb repressive complex 2 controls numerous cell cycle and regulatory genes through trimethylation of histone 3, which results in chromatin condensation and transcriptional silencing. EZH2 overexpression has been correlated with high incidence of more aggressive, metastatic prostate cancers. Although this correlation means EZH2 could prove valuable as a biomarker in clinical settings, the question remains whether EZH2 is actually responsible for the initiation of these more aggressive tumor types. In this study, EZH2-mediated neoplastic transformation of the normal prostate epithelial cell line benign prostate hyperplasia 1 (BPH1) was confirmed by in vivo tumor growth and in vitro colony formation. Furthermore, EZH2 transformation resulted in increased invasive behavior of BPH1 cells, indicating that EZH2 may be responsible for aggressive behavior in prostate cancers. BPH1 was also transformed with the classic oncogenes myristoylated Akt and activated Ras(V12) to allow phenotype comparisons with the EZH2-transformed cells. This study marks the first demonstration of neoplastic transformation in prostate cells mediated by EZH2 and establishes that EZH2 possesses stronger transforming activity than Akt but weaker activity than activated Ras. (Mol Cancer Res 2009;7(9):1456–65