Hypomethylation of the rat aryl sulfotransferase IV gene and amplification of a DNA sequence during multistage 2-acetylaminofluorene hepatocarcinogenesis

• Published in: Chemico-biological interactions Vol. 92; no. 1; pp. 363 - 370
• Main Authors: Yerokun, Tokunbo, Lyn-Cook, Beverly D., Ringer, David P.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.06.1994
• Subjects: 2-Acetylaminofluorene (AAF); 2-Acetylaminofluorene - toxicity; Animals; Aryl sulfotransferase IV (AST IV); Arylsulfotransferase - genetics; Chinese Hamster ovary cells (CHO cells); Cricetinae; DNA, Complementary - chemistry; DNA, Complementary - metabolism; Gene Amplification; Liver - drug effects; Liver - enzymology; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Methylation; Polymorphism, Restriction Fragment Length; Rats; Restriction fragment length polymorphism (RFLP); RNA, Messenger - genetics; Chinese Hamster ovary cells (CHO cells); Restriction fragment length polymorphism (RFLP); Aryl sulfotransferase IV (AST IV); 2-Acetylaminofluorene (AAF)
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/0009-2797(94)90077-9

Rat hepatic aryl sulfotransferase IV (AST IV), which catalyses sulfuric acid esterification of N-hydroxy-2-acetylaminofluorene to its ultimate carcinogenic form, is differentially expressed during multistep 2-acetylaminofluorene (AAF) hepatocarcinogenesis. Two molecular mechanisms associated with this effect involve modulation of mRNA translational capacity at the early stages, and gene transcription at the late stages of the carcinogenic process. To characterize further the molecular mechanisms that may be involved in the transient regulation of the enzyme expression, an AST IV cDNA was used to assess the change in methylation profile and restriction fragment length polymorphism (RFLP) in the gene domain of genomic DNA derived from rats at different stages of carcinogenesis. The onset of hypomethylation of the AST IV gene domain and amplification of a 5.3-kb DNA sequence was found to correlate with the stage in AAF hepatocarcinogenesis, where rats begin to exhibit irreversible loss in hepatic enzyme expression and the liver becomes committed to hepatoma formation. This represents the first observation of both altered methylation status of AST IV gene domain and amplification of a DNA sequence whose expression may play a role in the genesis and/or progression of neoplastic transformation of initiated cells during AAF hepatocarcinogenesis.