Hypermethylation of WRN Gene Promoter Linked to Human Cancer
Jun 25, 2006 cancer, environmental alterations, research articles
New research published in the Proceedings of the National Academy of Sciences suggests that increased methylation of the promoter sequence of the WRN gene is highly correlated with inactivation of the gene in human cancer cell lines.
- In this manuscript, we demonstrate that WRN undergoes CpG island promoter methylation-associated gene silencing in human cancer cells. The hypermethylation of the WRN promoter leads to its loss of expression and hypersensitivity to topoisomerase inhibitors and DNA-damaging agents. The epigenetic loss of WRN function can be rescued by the use of DNA-demethylating agents. Furthermore, the reintroduction of WRN into those transformed cell lines with WRN-deficiency due to hypermethylation provokes a reduction in colony formation and a decrease in growth of tumor xenografts, supporting the hypothesis that WRN has a tumor-suppressor role. The analysis of a large panel of human primary tumors (n = 630) shows that WRN CpG island hypermethylation is a common event in tumorigenesis. Most importantly, for colorectal cancer, the presence of aberrant methylation at the WRN promoter predicts improved survival in those patients treated with irinotecan, a topoisomerase inhibitor commonly used in this neoplasm. These findings underline the significance of WRN as a caretaker of our genome with tumor-suppressor activity and identify epigenetic silencing of WRN as a key step in cancer development that may have an important clinical influence on the treatment of these patients.
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