Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression

Deregulation of the pRB/E2F pathway, which occurs frequently in human malignancy, is often associated with inappropriate proliferation and/or apoptosis. While the role of E2F1 in apoptosis induction has been well-established, it remains unclear how this pro-apoptotic activity is regulated in cancer. Here we describe EZH2, an oncogenic polycomb histone methyltransferase and an E2F1 target, as an important regulator of E2F1-dependent apoptosis. We show that E2F1 induces EZH2 expression, which in turn antagonizes the induction of E2F1 pro-apoptotic target Bim expression. RNAi-mediated gene depletion of EZH2 enhances E2F1-dependent Bim expression, thereby promoting the pro-apoptotic activity of E2F1. Hence, the concomitant induction of EZH2 and Bim by E2F1 constitutes a fail-safe mechanism to allow tumor cells with aberrant E2F1 activity to evade apoptosis. These findings reveal a novel mechanism by which the apoptotic activity of E2F1 is restrained in human cancer and also provide the first evidence that EZH2 directly regulates apoptotic process in cancer cells. Cell Death and Differentiation (2010) 17, 801-810; doi:10.1038/cdd.2009.162; published online 6 November 2009