Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS

Marta Barradas, Emma Anderton, Juan Carlos Acosta, Side Li, Ana Banito, Marc Rodriguez-Niedenführ, Goedele Maertens, Michaela Banck, Ming-Ming Zhou, Martin J Walsh, Gordon Peters, Jesús Gil
Genes & Development 2009 May 15, 23 (10): 1177-82
The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members of the Polycomb group (PcG) of transcriptional repressors. Here we show that signaling from oncogenic RAS overrides PcG-mediated repression of INK4a by activating the H3K27 demethylase JMJD3 and down-regulating the methyltransferase EZH2. In human fibroblasts, JMJD3 activates INK4a, but not ARF, and causes p16(INK4a)-dependent arrest. In mouse embryo fibroblasts, Jmjd3 activates both Ink4a and Arf and elicits a p53-dependent arrest, echoing the effects of RAS in this system. Our findings directly implicate JMJD3 in the regulation of INK4a/ARF during oncogene-induced senescence and suggest that JMJD3 has the capacity to act as a tumor suppressor.

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