Highly conserved Methionine Adenosyltransferase (MAT) Isoenzymes
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It has been shown that changes of intracellular levels of S-adenosylmethionine (SAM) are related to the well beings of cells and organisms. The fluctuation of SAM level is cause by imbalance between SAM synthesis and metabolic pathways (methylation, transsulfuration and aminiopropylation) or degradation. S-adenosylmethionine biosynthesis is strictly and solely dependent on the activity of Methionine Adenosyltransferase (MAT, E.C.2.5.1.6), also known as S-adenosylmethionine synthetase. The methionine adenosyltransferase is encoded by two genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, α1 and α2. MAT1A is expressed in normal liver, and it encodes the α1 subunit found in two native MAT isozymes, which are either a dimer (MAT III) or tetramer (MAT I) of this single subunit.
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MAT2A encodes for a catalytic subunit (α2) found in a native MAT isozyme (MAT II), which is associated with a regulatory subunit (β) in encoded by MATA2B gene. MAT1A is expressed mostly in the adult normal hepatocytes, whereas MAT2A is widely distributed, of which mainly investigated are among highly proliferating liver cells, such as fetal liver and liver cancer cells. Except for parasites that rely on host for living, cells from all organisms have methionine adenyltransferase. MAT genes have been found to be exceptionally conserved throughout evolution. Enzymatic activity of MAT is critical in regulating the level of SAM and plays critical roles in methionine cycle and epigenetic study. In some situations expression of MAT1A or MAT2A have not changed yet the capability of synthesizing SAM are different. Therefore, measuring MAT activity is essential in evaluation the functions of MAT/SAM axis.
MAT-II is important for cell proliferation
Regulation of liver cell proliferation is a key event to control organ size during development and liver regeneration. MAT-II is an important enzyme in cellular metabolism and catalyzes the formation of S-adenosylmethionine (SAMe) from L-methionine and ATP. MAT2A is expressed in extrahepatic tissues. In adult liver, increased expression of MAT2A is associated with rapid growth or de-differentiation of the liver. The influence of MAT expression on liver growth and injury was further demonstrated using a MAT1A knockout mouse model (Martínez-Chantar, M.L, 2002. FASEB J. 16:1292). In this model, absence of hepatic MAT1A is compensated by induction of MAT2A. These animals exhibit chronic hepatic SAMe deficiency, are prone to liver injury and develop hepatocellular carcinoma (HCC).
In human HCC, both promoter hypomethylation and increased expression of c-Myb and Sp1 with subsequent trans-activation of the MAT2A promoter contribute to transcriptional up-regulation of MAT2A in HCC. Nuclear binding of NF-κB and AP-1 to the promoter of human glutamate-cysteine ligase catalytic subunit was increased in HCC. In HepG2 cells, a human hepatocellular carcinoma, both NF-kB and AP-1 are required for basal MAT2A expression and mediate the increase in MAT2A expression observed in response to TNF-α treatment (Yang H, Induction of Human Methionine Adenosyltransferase 2A Expression by Tumor Necrosis Factor α. J Biochem. 2003. 278:50887). Up-regulation of MAT2A provides growth improvement and S-adenosylmethionine and methylthioadenosine thus can block mitogenic signaling in colon cancer cells.
In H35 hepatoma cells, growth factors such as hepatocyte growth factor (HGF) and insulin up-regulated MAT2A expression. Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-phosphate kinase (PI 3-K) pathways were required for both HGF-induced cell proliferation and MAT2A up-regulation. The inhibition of these pathways was associated with the switch from the expression of fetal liver MAT2A to the adult liver MAT1A isoform. Treatment of H35 hepatoma cells with MAT2A antisense oligonucleotides decreased cell proliferation induced by HGF. Growth inhibitors such as transforming growth factor (TGFβ) blocked HGF-induced MAT2A up-regulation while increasing MAT1A mRNA levels in H35 cells. MAT2A expression is required for the process of liver cell proliferation (Paneda C, Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation. Hepatology. 2002 35:1381).
The consequence of the choline-deficient and ethionine-supplemented (CDE) diet is depletion of hepatic S-adenosylmethionine (SAM). After 48 h of the CDE diet, SAM levels decreased about half and MAT1/III disappeared via post-translational mechanisms, whereas MAT-II increased via pretranslational mechanisms. CDE-fed young mice exhibited extensive necrosis, edema, and acute pancreatic inflammatory infiltration and treatment by SAM can help prevent and recover the injury. Old female mice consuming the CDE diet that do not develop pancreatitis showed a similar fall in pancreatic SAM level. Although the pancreatic SAM level fell by more than 80% in the MAT1A knockout mice, no pancreatitis developed. MAT1A is highly expressed in the normal pancreas as well as pancreatic acini, which is in contrary to what we commonly believe that MAT-I/III is liver-specific. The CDE diet causes dramatic changes in the expression of MAT isozymes by different mechanisms. In contrast to the situation in the liver, where absence of MAT1A and decreased hepatic SAM level can lead to spontaneous tissue injury, in the pancreas the roles of SAM and MAT1A appear more complex and remain to be defined (Lu SC, Role of S-adenosylmethionine in two experimental models of pancreatitis. FASEB J 2003 17(1): 56). It is interesting to see age-dependent pathological changes in tissues. It might be related to the fact that normal human SAM level is also age dependent. As SAM is the sole methyl donor for the proper methylation of DNAs, RNAs, hormones, lipid proteins and neurotransmitters, reduced or depleted SAM level will definitely affect the normal methylation of critical bio-molecules through epigenetic mechanisms.
Epigenetic regulation of methionine adenosyltransferase and HCC therapy
MicroRNAs (miRNAs) and MAT1A are dysregulated in HCC, and reduced MAT1A expression correlates with worse HCC prognosis. Expression of miR-664, miR-485-3p, and miR-495, potential regulatory miRNAs of MAT1A, is increased in HCC. Knockdown of these miRNAs individually in Hep3B and HepG2 cells induced MAT1A expression, reduced growth, and increased apoptosis, while combined knockdown exerted additional effects. Subcutaneous and intraparenchymal injection of Hep3B cells stably overexpressing each of this trio of miRNAs promoted tumorigenesis and metastasis in mice. Treatment with miRNA-664 (miR-664), miR-485-3p, and miR-495 siRNAs reduced tumor growth, invasion, and metastasis in an orthotopic liver cancer model. 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. 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, HEPATOLOGY 2013. 57(5): 2081).
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