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

  1. Marta Barradas1,6,
  2. Emma Anderton2,6,
  3. Juan Carlos Acosta1,6,
  4. SiDe Li3,4,
  5. Ana Banito1,
  6. Marc Rodriguez-Niedenführ2,
  7. Goedele Maertens2,
  8. Michaela Banck5,
  9. Ming-Ming Zhou4,
  10. Martin J. Walsh3,4,
  11. Gordon Peters2,8 and
  12. Jesús Gil1,7
  1. 1Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, United Kingdom;
  2. 2Molecular Oncology Laboratory, CRUK London Research Institute, London WC2A 3PX, United Kingdom;
  3. 3Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA;
  4. 4Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USA;
  5. 5Department of Medicine, Division of Hematology and Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA
    1. 6

      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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