Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.
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.
Barradas
Marta
M
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, United Kingdom.
Anderton
Emma
E
Acosta
Juan Carlos
JC
Li
Side
S
Banito
Ana
A
Rodriguez-Niedenführ
Marc
M
Maertens
Goedele
G
Banck
Michaela
M
Zhou
Ming-Ming
MM
Walsh
Martin J
MJ
Peters
Gordon
G
Gil
Jesús
J
D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D015398:Signal Transduction; 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; D018631:ras Proteins