Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer
Open accessAbstract
Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumor-suppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylation-dependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors ( n = 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs.
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The WRN gene is often inactivated by epigenetic means in human cancers.
“Recent information indicates that the WRN gene is often inactivated by epigenetic means in human cancers 42”
From The common biology of cancer and ageing (2007) · cites this paper as [42]
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- Authors
- Agrelo, R., Cheng, W.-H., Setien, F., Ropero, S., Espada, J., Fraga, M. F., Herranz, M., Paz, M. F., Sanchez-Cespedes, M., Artiga, M. J., Guerrero, D., Castells, A., von Kobbe, C., Bohr, V. A., & Esteller, M.
- Affiliations
- *Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Melchor Fernandez Almagro 3, 28029 Madrid, Spain;
- National Institutes of Health (US)
- Spanish National Cancer Research Centre (ES)
- Servicio Navarro de Salud (ES)
- Hospital Clínic de Barcelona (ES)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-06-06
- Volume
- 103
- Issue
- 23
- Pages
- 8822-8827
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1466544
- OpenAlex
- W2142629409
- Cited by
- 264
- References
- 40
- Citations by year
- 2025: 7 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 8 · 2017: 13 · 2016: 10 · 2015: 14 · 2014: 18 · 2013: 21 · 2012: 22
- FWCI
- 11.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- Werner syndrome, WRN gene, epigenetic silencing, CpG island hypermethylation, transcriptional silencing, chromosomal instability, topoisomerase inhibitors, irinotecan, DNA demethylation, tumor suppressor, colorectal cancer, RecQ helicase, apoptosis, nude mouse xenograft, tumor growth inhibition
- MeSH terms
- Werner Syndrome Helicase, Irinotecan, Animals, Camptothecin, Colonic Neoplasms, DNA Helicases, Exodeoxyribonucleases, Female, Humans, Mice, Nude, Promoter Regions, Genetic, RNA, Messenger, Werner Syndrome, Genes, Tumor Suppressor, CpG Islands, DNA Methylation, Aging, Premature, Epigenesis, Genetic, Cell Line, Tumor, Mice, RecQ Helicases, Topoisomerase I Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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