Hypomethylation of and by downregulation of results in restriction of liver carcinogenesis by amarogentin treatment.

Amarogentin (active component of ) was found to prevent CCl4/NDEA-induced liver carcinogenesis at mild dysplastic stage through modulation of cell cycle, apoptosis, self-renewal pathways. The cell cycle regulatory genes , P16 and RBSP3 were found to be upregulated in restricted liver lesions. To understand the mechanism of upregulation during restriction of cacinogenesis, the effect of amarogentin on epigenetic modification was evaluated in this study. It was also validated . Hypermethylation of and was seen in mouse hepatocellular carcinoma (30th week carcinogen control mice); however, hypomethylation of these genes was seen in amarogentin-treated liver. In the case of , no such change was seen. expression (mRNA/protein) was significantly increased in later stages of carcinogenesis, whereas its expression was comparable to normal liver in the case of amarogentin treatment. No significant change in expression (mRNA/protein) of was observed irrespective of treatment. Amarogentin treatment upregulated the expression (mRNA/protein) of , and in the HepG2 cell line. Here also treated cells showed and hypomethylation with downregulation. Increased expression of , and after treating cells with demethylating agent 5-aza-2-deoxycytidine indicated epigenetic modulation by amarogentin treatment.