Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Barradas M*, Anderton E*, Acosta JC*, Li S, Banito A, Rodriguez-Niedenfuhr M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G, and Gil J2009-05-14T22:00:00Z<h3>​Abstract</h3><div><br></div><div>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.<br></div><p><br></p><p>​Genes Dev, 2009. 23(10): p. 1177-82. <br></p>382