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Cell Death Differ. 2010 May;17(5):801-10. doi: 10.1038/cdd.2009.162. Epub 2009 Nov 6.

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

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Genome Institute of Singapore, Biopolis, Singapore.


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.

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