Details

Autor(en) / Beteiligte

• Agrelo, Ruben
• Cheng, Wen-Hsing
• Setien, Fernando
• Ropero, Santiago
• Espada, Jesus
• Fraga, Mario F.
• Herranz, Michel
• Paz, Maria F.
• Sanchez-Cespedes, Montserrat
• Artiga, Maria Jesus
• Guerrero, David
• Castells, Antoni
• von Kobbe, Cayetano
• Bohr, Vilhelm A.
• Esteller, Manel

Titel

Epigenetic Inactivation of the Premature Aging Werner Syndrome Gene in Human Cancer

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2006-06, Vol.103 (23), p.8822-8827

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 tumorsuppressor 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 methylationdependent 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.