The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
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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Cites
The fundamental role of epigenetic events in cancer
Jones, P. A., & Baylin, S. B. (2002) · Nature Reviews Genetics · doi:10.1038/nrg816 · Cited by 5,648
Self-citationMethylation-specific PCR: a novel PCR assay for methylation status of CpG islands.
Herman, J. G., Graff, J. R., Myöhänen, S., Nelkin, B. D., & Baylin, S. B. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.18.9821 · Cited by 5,634
Self-citationActivation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC
Morin, P. J., Sparks, A. B., Kořínek, V., Barker, N., Clevers, H. C., Vogelstein, B., & Kinzler, K. W. (1997) · Science · doi:10.1126/science.275.5307.1787 · Cited by 4,000
β-Catenin regulates expression of cyclin D1 in colon carcinoma cells
Tetsu, O., & McCormick, F. (1999) · Nature · doi:10.1038/18884 · Cited by 3,601
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510
Gene Silencing in Cancer in Association with Promoter Hypermethylation
Herman, J. G., & Baylin, S. B. (2003) · New England Journal of Medicine · doi:10.1056/nejmra023075 · Cited by 3,471
Self-citationStress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239
Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC −/− Colon Carcinoma
Korinek, V., Barker, N., Morin, P. J., van Wichen, D., de Weger, R., Kinzler, K. W., Vogelstein, B., & Clevers, H. (1997) · Science · doi:10.1126/science.275.5307.1784 · Cited by 2,905
Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase
Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., & Mayo, M. W. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600244 · Cited by 2,750
hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S., Frye, R. A., Pandita, T. K., Guarente, L., & Weinberg, R. A. (2001) · Cell · doi:10.1016/s0092-8674(01)00527-x · Cited by 2,690
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Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum
James, S. J., Shpyleva, S., Melnyk, S., Pavliv, O., & Pogribny, I. P. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.8 · Cited by 100
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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