Werner syndrome gene had been epigeneitcally inactivated in human cancer

by Jane Cheung. Student number: 40092869

Werner Syndrome (WS) is a very rare genetic disorder which only occur around three in every one million people worldwide. It is characterized by premature aging and high incidence of cancer. WS is caused by mutations in the WS gene (WRN) and the function of the WRN protein is lost due to the mutation.

CpG islands are a short region of DNA that contains many cytidine and guanosine in the nucleotides. It is located near the promoter region and majority of them are associated with genes that are essential for general cell functions. Under normal conditions, CpG islands will remains unmethylated, allowing expression of the particular gene. In cancer cells, some CpG islands will become hypermethlated and the function of the gene will be inactivated.

In this report by Agerlo et al, it showed that CpG island hypermethylation had inactivated the function of WRN in many tumor cells. This inactivation caused WRN lost its exonuclease activity and chromosomes become more unstable. Furthermore, these hypermethylation-deficient WRN cancer cells will die if they were exposed to topoisomerase inhibitors. They also showed that by adding a DNA-demethylating agent or WRN into these hypermethylation-deficient WRN cancer cells, the growth of the tumor-cell was inhibited and the density of the tumor was reduced. This indicated that WRN has tumor-suppressor gene features. Also, the colon cancer patients with WRN CpG island hypermethylation had a better response to the camptothecin analogue, irinotecan, than the patents without WRN CpG island hypermethylation. Furthermore, WRN CpG island hypermethylation was commonly present in epithelial and mesenchymal tumors by screening a large amount of human tumors. All of these findings further confirmed the close connection between aging and cancer.

References:

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

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

Proc Natl Acad Sci U S A. 2006 June 6; 103(23): 8822–8827.