Elevated expression and altered pattern of activity of DNA methyltransferase in liver tumors of rats fed methyl-deficient diets

DNA methyltransferase (MTase) activity in nuclear extracts from neoplasticand preneoplastic livers of rats fed a methyl-deficient diet (MDD) iselevated compared with that seen in the livers of control rats. Nuclearproteins were prepared in the presence of protease inhibitors includingtrans-epoxy succinyl-L-leucylamido-(4- guanido)butane and were fractionatedby isoelectric focusing. In normal, control liver, two distinct MTasefractions were observed. In MDD-induced malignant liver, a third fraction,in addition to the previous two, was also seen. Both the DNA substrate andthe cytosine site specificities of the third MTase fraction differ fromthose of the other two fractions. The distinct MTase activity in livertumor has significantly more de novo MTase activity than do the MTasefractions of normal, control liver. Thus, normal and neoplastic rat liversdiffer in DNA MTase fractionation patterns and site specificities. Thealtered DNA MTase activity observed in rat liver tumors caused by MDDs maybe one of the critical factors contributing to cancer formation throughabnormal DNA methylation.