Frequent hypermethylation of the 5' CpG island of the mitotic stress checkpoint gene Chfr in colorectal and non-small cell lung cancer.
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.
Corn
Paul G
PG
University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Summers
Matthew K
MK
Fogt
Franz
F
Virmani
Arvind K
AK
Gazdar
Adi F
AF
Halazonetis
Thanos D
TD
El-Deiry
Wafik S
WS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D008938:Mitosis; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases