Blocking MAT1A induction significantly reduced the antitumorigenic effect of miR–495 siRNA, whereas maintaining MAT1A expression prevented miRNA–mediated enhancement of growth and metastasis. Knockdown of these miRNAs increased total and nuclear level of MAT1A

protein, global CpG methylation, lin–28 homolog B (Caenorhabditis elegans) (LIN28B) promoter methylation, and reduced LIN28B expression. The opposite occurred with forced expression of these miRNAs. In conclusion, upregulation of miR–664, miR–485–3p, and miR–495 contributes to lower MAT1A expression in HCC, and enhanced tumorigenesis may provide potential targets for HCC therapy. Yang H, Cho ME, Li TW, Peng H, Ko KS, Mato JM, et al. MicroRNAs regulate Napabucasin concentration methionine adenosyltransferase Forskolin mouse 1A expression in hepatocellular carcinoma. J Clin Invest. 2013;123:285–298. (Reprinted with permission.) Integrity of the hepatic

epigenome is a key component of organ homeostasis. Disruption of this integrity is believed to be a fundamental driver predisposing many chronic liver diseases to cancer development.1 Consistently, early changes in DNA methylation patterns are observed during malignant transformation preceding allelic imbalances and leading to cancer progression.2 In line with this, methionine metabolism and labile methyl groups play crucial roles in hepatocarcinogenesis and are frequently associated with a significant decrease in levels of S–adenosyl–L–methionine (SAMe), the principal methyl donor in mammals.3 Methionine adenosyltransferase (MAT) is the major enzyme catalyzing the synthesis of SAMe, thereby regulating many biological processes, including proliferation Niclosamide and differentiation.4

MAT activity in mammals is associated with two gene products, MAT1A and MAT2A, which display a tissue–specific expression pattern. MAT1A is associated with high SAMe levels and is exclusively expressed in the adult liver, whereas MAT2A results in lower SAMe levels and is the main source of extrahepatic SAMe synthesis. High .levels of MAT2A are also detected during differentiation of fetal livers, where its expression is progressively replaced by MAT1A upon liver maturation.5 Conversely, a switch in MAT gene expression is observed during liver regeneration and hepatocarcinogenesis, which mimics the fetal expression pattern and causes re–expression of MAT2A in place of the liver–specific MAT1A. This oncofetal switch in MAT gene expression is partly regulated by HuR/methyl–HuR and AUF1 during dedifferentiation, development, as well as proliferation and confers to a growth advantage for tumor cells.6 Decreased MAT1A expression and subsequent up–regulation of MAT2A is also observed in hepatoma cell lines, rodent HCCs, and chronic human liver diseases such as liver cirrhosis and HCC.3, 7 Consistently, MAT1A–deficient mice with low SAMe levels are prone to liver injury, steatosis, and tumorigenesis.