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.