ArticleProceedings of the National Academy of Sciences of the United States of America2006
Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed, 262 citations in OpenAlex.
- Ocular Manifestations in Patients with Werner Syndrome.International journal of molecular sciences · 2026Review
- DNA Damage and Repair in Thyroid Physiology and Disease.Endocrine reviews · 2026Review
- Prognostic Significance of DNA Repair Gene mRNA Expression in Early-Stage Breast Cancer: Insights into Clinical Relevance.Oncology research · 2026Article
- Cancer and Aging Biomarkers: Classification, Early Detection Technologies and Emerging Research Trends.Biosensors · 2025Review
- Defining aging-associated factors that increase susceptibility to prostate cancer.Endocrine-related cancer · 2025Review
- Targeting the Werner syndrome protein in microsatellite instability cancers: mechanisms and therapeutic potential.Clinical and experimental medicine · 2025Review
- Whole Exome Sequencing Identifies a Novel Frameshift Mutation of the WRN Gene in a Werner Syndrome Family and Functional Analysis.Molecular genetics & genomic medicine · 2025Article
- Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer.DNA repair · 2025Review
- PLK1 phosphorylates WRN at replication forks.The Journal of pharmacology and experimental therapeutics · 2025Article
- Review
- WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI).Cancer treatment and research · 2023Article
- Epigenetics, DNA damage, and aging.The Journal of clinical investigation · 2022Review
- Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer.Cells · 2022Review
- Non-enzymatic function of WRN RECQL helicase regulates removal of topoisomerase-I-DNA covalent complexes and triggers NF-κB signaling in cancer.Aging cell · 2022Article
- CDK1 and HSP90AA1 Appear as the Novel Regulatory Genes in Non-Small Cell Lung Cancer: A Bioinformatics Approach.Journal of personalized medicine · 2022Article
- RecQ Helicase Somatic Alterations in Cancer.Frontiers in molecular biosciences · 2022Review
- Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia.Molecular cytogenetics · 2021Article
- Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy.Molecules (Basel, Switzerland) · 2021Article
- Article
- WRN inhibits oxidative stress-induced apoptosis of human lensepithelial cells through ATM/p53 signaling pathway and its expression is downregulated by DNA methylation.Molecular medicine (Cambridge, Mass.) · 2020Article
51 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.