CpG dinucleotide methylation of the CYP19 I.3/II promoter modulates cAMP-stimulated aromatase activity.
Aromatase expression varies in a tissue-specific manner and among individuals. Aromatase promoter I.3/II, regulated by a cAMP response element (CRE), is normally quiescent in human skin fibroblasts, whereas its hyperactivity may cause local or systemic estrogen excess. We describe the methylation status of 6 CpG dinucleotides within a 571-bp fragment of promoter I.3/II containing a CRE in cAMP-responsive (n=1) or nonresponsive (n=3) primary skin fibroblasts cultured from healthy volunteers. Four out of 6 CpG dinucleotides were unmethylated in cAMP-responsive fibroblasts, whereas all 6 CpG dinucleotides were hypermethylated in cAMP-nonresponsive fibroblasts. Basal and cAMP-stimulated aromatase activity and promoter I.3/II activation were significantly higher in the presence of unmethylated DNA. Furthermore, methylation at the CRE interfered with CREB binding. Thus, methylation of CpG dinucleotides within promoter I.3/II regulates aromatase expression and may be one source of inter-individual variability. Furthermore, abnormal methylation of the aromatase promoter may contribute to aromatase overexpression in breast cancer.
Demura
Masashi
M
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Suite 4-123, Chicago, IL 60611-3095, USA.
Bulun
Serdar E
SE
D001141:Aromatase / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics*; D000242:Cyclic AMP / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D015533:Transcriptional Activation / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D000242:Cyclic AMP; D001141:Aromatase