Carcinogenesis, Vol. 24, No. 1, 47-51,
January 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Frequent hypermethylation of the 5' CpG island of the mitotic stress checkpoint gene Chfr in colorectal and non-small cell lung cancer
1 University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA,
2 Graduate Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, PA 19104, USA,
3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA,
4 The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA and
5 Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Genetics, Pharmacology, Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Chfr, a mitotic stress checkpoint gene, regulates a prophase delay in cells exposed to agents that disrupt microtubules, such as nocodazole and taxol. In the present study, we report that Chfr is frequently methylated in cell lines derived from tumors of the colon (80%), brain (100%) and bone (100%). In addition, Chfr was methylated in 37% of primary colon adenocarcinomas and in 10% of primary non-small cell lung carcinomas. In normal colon tissue, but not lung, there was evidence for age-related methylation of Chfr, suggesting that in some cases the tumor may have arisen from a methylated clonal precursor. Methylation was associated with loss of Chfr mRNA and protein expression in cancer cell lines. In cells with methylated Chfr, treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in re-expression of Chfr, and partial restoration of the prophase checkpoint. These results suggest that epigenetic inactivation of Chfr may be responsible for many of the checkpoint defects observed in human cancers.
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