Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS
- Marta Barradas1,6,
- Emma Anderton2,6,
- Juan Carlos Acosta1,6,
- SiDe Li3,4,
- Ana Banito1,
- Marc Rodriguez-Niedenführ2,
- Goedele Maertens2,
- Michaela Banck5,
- Ming-Ming Zhou4,
- Martin J. Walsh3,4,
- Gordon Peters2,8 and
- Jesús Gil1,7
- 1Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, United Kingdom;
- 2Molecular Oncology Laboratory, CRUK London Research Institute, London WC2A 3PX, United Kingdom;
- 3Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA;
- 4Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USA;
- 5Department of Medicine, Division of Hematology and Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA
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↵6 These authors contributed equally to this work.
Abstract
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 p16INK4a-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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Footnotes
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↵7 Corresponding authors.
↵E-MAIL jesus.gil{at}csc.mrc.ac.uk; FAX 44-20-8383-8306.
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↵8 E-MAIL gordon.peters{at}cancer.org.uk; FAX 44-207-269-3094.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.511109.
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Supplemental material is available at http://www.genesdev.org.
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- Received October 21, 2008.
- Accepted April 3, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press