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Methionine adenosyltransferases in liver cancer.

ABSTRACT: Methionine adenosyltransferases (MATs) are essential enzymes for life as they produce S-adenosylmethionine (SAMe), the biological methyl donor required for a plethora of reactions within the cell. Mammalian systems express two genes, MAT1A and MAT2A, which encode for MAT?1 and MAT?2, the catalytic subunits of the MAT isoenzymes, respectively. A third gene MAT2B, encodes a regulatory subunit known as MAT? which controls the activity of MAT?2. MAT1A, which is mainly expressed in hepatocytes, maintains the differentiated state of these cells, whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver (e.g., hepatic stellate and Kupffer cells). The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MAT?1. A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation, but this change in the expression pattern of MATs results in reduced hepatic SAMe level. Decades of study have utilized the Mat1a-knockout (KO) mouse that spontaneously develops non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis. An increasing volume of work indicates that MATs have SAMe-independent functions, distinct interactomes and multiple subcellular localizations. Here we aim to provide an overview of MAT biology including genes, isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation. We will highlight recent breakthroughs in the field and underscore the importance of MAT's in liver tumorigenesis as well as their potential as targets for cancer therapy.

SUBMITTER: Murray B

PROVIDER: S-EPMC6710175 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Methionine adenosyltransferases in liver cancer.

Murray Ben B Barbier-Torres Lucia L Fan Wei W Mato José M JM Lu Shelly C SC

World journal of gastroenterology 20190801 31

Methionine adenosyltransferases (MATs) are essential enzymes for life as they produce S-adenosylmethionine (SAMe), the biological methyl donor required for a plethora of reactions within the cell. Mammalian systems express two genes, MAT1A and MAT2A, which encode for MATα1 and MATα2, the catalytic subunits of the MAT isoenzymes, respectively. A third gene MAT2B, encodes a regulatory subunit known as MATβ which controls the activity of MATα2. MAT1A, which is mainly exp ...[more]

PMID: 31496615

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Project description:Methionine adenosyltransferase (MAT) is the cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM), the principal biological methyl donor and a key regulator of hepatocyte proliferation, death and differentiation. Two genes, MAT1A and MAT2A, encode 2 distinct catalytic MAT isoforms. A third gene, MAT2B, encodes a MAT2A regulatory subunit. In hepatocellular carcinoma (HCC), MAT1A downregulation and MAT2A upregulation occur, known as the MAT1A:MAT2A switch. The switch is accompanied with an increasing expression of MAT2B, which results in decreased SAM levels and facilitates cancer cell growth. Berberine, an isoquinoline alkaloid isolated from many medicinal herbs such as Coptis chinensis, has a wide range of pharmacological effects including anti-cancer effects. Because drug-induced microRNAs have recently emerged as key regulators in guiding their pharmacological effects, we examined whether microRNA expression is differentially altered by berberine treatment in HCC. In this study, we used microRNA microarrays to find that the expression level of miR-21-3p (previously named miR-21*) increased after berberine treatment in the HepG2 human hepatoma cell line. To predict the putative targets of miR-21-3p, we integrated the gene expression profiles of HepG2 cells after berberine treatment by comparing with a gene list generated from sequence-based microRNA target prediction software. We then confirmed these predictions through transfection of microRNA mimics and a 3' UTR reporter assay. Our findings provide the first evidence that miR-21-3p directly reduces the expression of MAT2A and MAT2B by targeting their 3' UTRs. In addition, an overexpression of miR-21-3p increased intracellular SAM contents, which have been proven to be a growth disadvantage for hepatoma cells. The overexpression of miR-21-3p suppresses growth and induces apoptosis in HepG2 cells. Overall, our results demonstrate that miR-21-3p functions as a tumor suppressor by directly targeting both MAT2A and MAT2B, indicating its therapeutic potential in HCC.

Dataset Information

Methionine adenosyltransferases in liver cancer.

Publications

Methionine adenosyltransferases in liver cancer.

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