The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.
The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A-ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS-RAF signaling pathway. JMJD3 is recruited to the INK4A-ARF locus and contributes to the transcriptional activation of p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.
Agger
Karl
K
Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Cloos
Paul A C
PA
Rudkjaer
Lise
L
Williams
Kristine
K
Andersen
Gitte
G
Christensen
Jesper
J
Helin
Kristian
K
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D009857:Oncogenes / Q000502:physiology*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C523761:Kdm6b protein, mouse; D010089:Oxidoreductases, N-Demethylating; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D018631:ras Proteins