CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors.
To determine if: (1) 5' CpG island methylation is related to Fhit inactivation; (2) there are tumor or carcinogen-specific methylation patterns, we examined 35 CpG sites in the promoter, exon and intron 1 of the mouse Fhit gene. In primary tumors of lung, urinary bladder and tongue, induced by different carcinogens, 15-35% of sites were methylated, with specific methylation patterns associated with each cancer type, suggesting cancer- or tissue-specific methylation patterns. The methylation patterns were associated with reduced Fhit expression, as determined by immunohistochemical analyses. Methylation of rat Fhit 5' CpGs in mammary adenocarcinomas, detected by methylation specific PCR amplification, also correlated with reduced gene expression. Thus, there was an overall association between promoter/exon 1 methylation and decreased Fhit expression. In contrast, in cancer-derived cell lines 70-95% of the CpG sites were methylated. This is the first detailed study of the relationship between Fhit 5' CpG island methylation and Fhit expression in murine tumors, our main models for preclinical cancer studies, and provides evidence that loss of Fhit expression and methylation are correlated in these mouse models and these models will be useful to examine the complex relationships among gene expression, methylation patterns and organ specificity.
Han
Shuang-Yin
SY
Kimmel Cancer Center, Thomas Jefferson University, 1008 BLSB, 233S. 10th Street, Philadelphia, PA 19107, USA.
Iliopoulos
Dimitrios
D
Druck
Teresa
T
Guler
Gulnur
G
Grubbs
Clinton J
CJ
Pereira
Michael
M
Zhang
Zhongqiu
Z
You
Ming
M
Lubet
Ronald A
RA
Fong
Louise Y Y
LY
Huebner
Kay
K
D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D000818:Animals; D019175:DNA Methylation; D015870:Gene Expression / Q000502:physiology*; D005809:Genes, Regulator; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase