Abstract
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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Abbreviations
- APAF1:
-
apoptosis protease-activating factor 1
- ARF:
-
alternative reading frame
- BH3:
-
BCL-2 homology 3
- EZH2:
-
enhancer of zeste homolog 2
- HDAC:
-
histone deacetylase
- MDM2:
-
human homolog of mouse double minute 2
- MCL-1:
-
myeloid leukemia cell differentiation protein 1
- PI3K:
-
phosphatidylinoditol-3-kinase
- PRC2:
-
polycomb repressive complex 2
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Acknowledgements
We thank Dr Kristian Helin (European Institute of Oncology, Milan) for the ER-E2F1 plasmids and Dr Claudio Brancolini for providing the IMR90/E1A cells. This work was supported by the Agency for Science, Technology and Research of Singapore.
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Wu, Z., Zheng, S., Li, Z. et al. Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell Death Differ 17, 801–810 (2010). https://doi.org/10.1038/cdd.2009.162
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DOI: https://doi.org/10.1038/cdd.2009.162
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