Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS
Open accessAbstract
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.
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Epigenetic regulation of INK4/ARF locus is not limited to polycomb proteins; other epigenetic regulators such as ZRF, MLL1 or JMJD3 are also involved.
“Epigenetic regulation of the INK4/ARF locus is not limited to polycomb proteins as other epigenetic regulators such as ZRF, MLL1 or JMJD3 are also involved in its regulation (Gil and Peters, 2006; Agger et al., 2009; Barradas et al., 2009; Kotake et al., 2009; Ribeiro et al., 2013).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Barradas et al., 2009
During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2, and recruitment of JMJD3 lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.
“During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2 [83], and recruitment of JMJD3 [84,85], a histone lysine demethylase that catalyzes H3K27 demethylation, lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [85]
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References 36 · Cited by 352
- Authors
- Barradas, M., Anderton, E., Acosta, J. C., Li, S., Banito, A., Rodriguez-Niedenführ, M., Maertens, G., Banck, M., Zhou, M.-M., Walsh, M. J., Peters, G., & Gil, J.
- Affiliations
- Imperial College London (GB)
- Cancer Research UK (GB)
- Icahn School of Medicine at Mount Sinai (US)
- Mount Sinai Hospital (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2009-05-15
- Volume
- 23
- Issue
- 10
- Pages
- 1177-1182
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2685533
- OpenAlex
- W2153019757
- Cited by
- 352
- References
- 36
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 12 · 2023: 9 · 2022: 7 · 2021: 18 · 2020: 14 · 2019: 20 · 2018: 18 · 2017: 24 · 2016: 26 · 2015: 17 · 2014: 30 · 2013: 27 · 2012: 35
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- U.S. Department of Defense
- Cancer Research UK
- National Institutes of Health
- Medical Research Council
- Fundação para a Ciência e a Tecnologia
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- JMJD3, H3K27 demethylase, INK4a/ARF locus, oncogenic Ras, Polycomb group proteins, EZH2, H3K27 methylation, cellular senescence, oncogene-induced senescence, p16INK4a, p53, tumor suppressor, epigenetic regulation, transcriptional repression
- MeSH terms
- Animals, Fibroblasts, Gene Expression Regulation, Humans, Oxidoreductases, N-Demethylating, Signal Transduction, Cellular Senescence, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, Epigenesis, Genetic, Mice, Jumonji Domain-Containing Histone Demethylases
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