CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers.
Cytochrome P450 (CYP) 1A1 (CYP1A1) and CYP1B1, dioxin-inducible CYP1s, are associated with carcinogenesis in extrahepatic tissues. CYP1B1 is featured in carcinogenesis of hormone-responsive tissues, where the CYP1B1 level is considerably high. Although aberrant expression of these enzymes is also observed in cancers that are not related to hormone response, their roles in carcinogenesis are not yet fully understood. We examined DNA methylation status of the CpG islands within the 5'-flanking region of the CYP1B1 and CYP1A1 genes in 7 colorectal cancer cell lines and 40 primary colorectal cancers. By bisulfite-modified direct sequencing, CYP1B1 gene methylation was detected in 2 cell lines (SW48 and Caco-2) and 2 (5%) cancers, but not in corresponding normal tissues. Treatment of the cells with 5-aza-2'-deoxycytidine revealed a clear increase in the CYP1B1 mRNA levels in SW48 and Caco-2 cells, while the amount of methylated alleles decreased. Only HT29 cells showed a clear increase in CYP1A1 mRNA, although there were no apparent differences in methylation status among these cell lines. None of these cell lines showed significant change in mRNA levels of aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT), which are known to directly activate CYP1 transcription. This observation suggested that expression of CYP1B1, but not CYP1A1, was downregulated by promoter methylation rather than decreased expression of AhR/ARNT. In conclusion, CpG methylation of the CYP1B1 promoter region epigenetically regulates CYP1B1 expression during development of some colorectal cancers. Moreover, cancers with aberrant CYP1B1 expression might show altered response to procarcinogen metabolism and chemotherapy.
Habano
Wataru
W
Department of Pharmacodynamics and Molecular Genetics, School of Pharmaceutical Sciences, Iwate Medical University, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan. whabano@iwate-med.ac.jp
Gamo
Toshie
T
Sugai
Tamotsu
T
Otsuka
Koki
K
Wakabayashi
Go
G
Ozawa
Shogo
S
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000502:physiology*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology*; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1