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Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation
Open accessAbstract
The class III histone deactylase (HDAC), SIRT1, has cancer relevance because it regulates lifespan in multiple organisms, down-regulates p53 function through deacetylation, and is linked to polycomb gene silencing in Drosophila. However, it has not been reported to mediate heterochromatin formation or heritable silencing for endogenous mammalian genes. Herein, we show that SIRT1 localizes to promoters of several aberrantly silenced tumor suppressor genes (TSGs) in which 5' CpG islands are densely hypermethylated, but not to these same promoters in cell lines in which the promoters are not hypermethylated and the genes are expressed. Heretofore, only type I and II HDACs, through deactylation of lysines 9 and 14 of histone H3 (H3-K9 and H3-K14, respectively), had been tied to the above TSG silencing. However, inhibition of these enzymes alone fails to re-activate the genes unless DNA methylation is first inhibited. In contrast, inhibition of SIRT1 by pharmacologic, dominant negative, and siRNA (small interfering RNA)-mediated inhibition in breast and colon cancer cells causes increased H4-K16 and H3-K9 acetylation at endogenous promoters and gene re-expression despite full retention of promoter DNA hypermethylation. Furthermore, SIRT1 inhibition affects key phenotypic aspects of cancer cells. We thus have identified a new component of epigenetic TSG silencing that may potentially link some epigenetic changes associated with aging with those found in cancer, and provide new directions for therapeutically targeting these important genes for re-expression.
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“evidence from cell culture models indicates that Sirt1 is involved in heterochromatin formation and might be particularly important in the silencing of certain tumour suppressors 45, 46”
From The common biology of cancer and ageing (2007) · cites this paper as [46]
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Metadata
- Authors
- Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S.-H. L., Watkins, D. N., Herman, J. G., & Baylin, S. B.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Baylin, Stephen B
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-03-31
- Volume
- 2
- Issue
- 3
- Pages
- e40
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC1420676
- OpenAlex
- W2091685314
- Cited by
- 387
- References
- 56
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 10 · 2019: 17 · 2018: 13 · 2017: 8 · 2016: 22 · 2015: 27 · 2014: 20 · 2013: 37 · 2012: 28
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Johns Hopkins University
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- SIRT1, class III histone deacetylase, tumor suppressor gene silencing, epigenetic silencing, histone acetylation, SIRT1 inhibition, cancer epigenetics, breast cancer, colon cancer, aging
- MeSH terms
- Antimetabolites, Antineoplastic, Breast Neoplasms, Colonic Neoplasms, Female, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, CpG Islands, DNA Methylation, Gene Silencing, Sirtuins, Epigenesis, Genetic, HCT116 Cells, Sirtuin 1
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