Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene
Open accessAbstract
A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 30-40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15(INK4B) and p16(INK4A), but not p14(ARF), inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15(INK4B) locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15(INK4B) locus, increases the expression of p15(INK4B), but not p16(INK4A) or p14(ARF), and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15(INK4B) locus.
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Expression of ARF is regulated by p53 via a negative feedback loop.
“Expression of ARF is regulated by p53 via a negative feedback loop (Kotake et al., 2011).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kotake et al., 2011
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- Authors
- Kotake, Y., Nakagawa, T., Kitagawa, K., Suzuki, S., Liu, N., Kitagawa, M., & Xiong, Y.
- Affiliations
- Hamamatsu University School of Medicine (JP)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Kitagawa, M
- Xiong, Y
- Venue
- Oncogene
- Published
- 2010-12-13
- Volume
- 30
- Issue
- 16
- Pages
- 1956-1962
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3230933
- OpenAlex
- W2001730700
- Cited by
- 1,001
- References
- 36
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 33 · 2023: 34 · 2022: 43 · 2021: 66 · 2020: 78 · 2019: 87 · 2018: 96 · 2017: 90 · 2016: 95 · 2015: 100 · 2014: 88 · 2013: 75 · 2012: 57
- FWCI
- 15.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (21590062, 22300329)
- National Cancer Institute (CA68377, R01CA068377)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ANRIL, long non-coding RNA, polycomb repressive complex 2, SUZ12, CDKN2B, tumor suppressor gene silencing, chromosome 9p21, oncogenic Ras, H3K27me3, Polycomb repression, gene expression regulation, cell proliferation
- MeSH terms
- Genetic Vectors, Humans, Genes, Tumor Suppressor, Gene Silencing, RNA, Untranslated, Cyclin-Dependent Kinase Inhibitor p15
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