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

Marta Barradas, Emma Anderton, Juan Carlos Acosta, Si De Li, Ana Banito, Marc Rodriguez-Niedenführ, Goedele Maertens, Michaela Banck, Ming Ming Zhou, Martin J. Walsh, Gordon Peters, Jesús Gil

Research output: Contribution to journalArticlepeer-review

249 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1177-1182
Number of pages6
JournalGenes and Development
Volume23
Issue number10
DOIs
StatePublished - May 15 2009

Keywords

  • Histone methylation
  • INK4a
  • JmjC proteins
  • Polycomb
  • Senescence

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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