Hypermethylation of the inhibin alpha-subunit gene in prostate carcinoma.
Inhibin is composed of an alpha- and a beta-subunit. Transgenic studies assigned a tumor-suppressive role to the inhibin alpha-subunit, and in human prostate cancer inhibin alpha-subunit gene expression was down-regulated. This study examined the inhibin alpha-subunit gene promoter and gene locus to determine whether promoter hypermethylation or LOH occurred in DNA from prostate cancer. The 5'-untranslated region of the human inhibin alpha-subunit gene was sequenced and shown to be highly homologous to the bovine, rat, and mouse inhibin alpha-subunit promoter sequences. A 135-bp region of the human promoter sequence that continued a cluster of CpG sites was analyzed for hypermethylation. Significant (P < 0.001) hypermethylation of the inhibin alpha-subunit gene promoter occurred in DNA from Gleason pattern 3, 4, and 5 carcinomas compared with nonmalignant tissue samples. A subset of the carcinomas with a cribriform pattern were unmethylated. LOH at 2q32-36, the chromosomal region harboring the inhibin alpha-subunit gene, was observed in 42% of prostate carcinomas. These data provide the first demonstration that promoter hypermethylation and LOH are associated with the inhibin alpha-subunit gene and gene locus in prostate cancer.
Schmitt
Jacqueline F
JF
Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia.
Millar
Douglas S
DS
Pedersen
John S
JS
Clark
Susan L
SL
Venter
Deon J
DJ
Frydenberg
Mark
M
Molloy
Peter L
PL
Risbridger
Gail P
GP
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001706:Biopsy; D002417:Cattle; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D007265:Inhibins / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051381:Rats; D012689:Sequence Homology, Nucleic Acid
D020121:5' Untranslated Regions; C094377:inhibin-alpha subunit; D007265:Inhibins