Methionine adenosyltransferases in liver cancer  

作　　者：Ben Murray Lucia Barbier-Torres Wei Fan JoséM Mato Shelly C Lu 

机构地区：[1]Division of Digestive and Liver diseases,Department of Medicine,Cedars-Sinai Medical Center,Los Angeles,CA 90048,United States [2]CIC bioGUNE,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas(Ciberehd),Technology,Park of Bizkaia,Derio 48160,Bizkaia,Spain

出　　处：《World Journal of Gastroenterology》2019年第31期4300-4319,共20页世界胃肠病学杂志（英文版）

基　　金：National Institutes of Health,NIAAA,No.R01AA026759(Lu);National Institutes of Health,NIDDK,No.R01DK107288(Lu);National Institutes of Health,NCCIH,No.R01AT001576;National Institutes of Health,NCI,No.R01CA172086(Lu and Mato);Agencia Estatal de Investigación MINECO,No.SAF 2017-88041-R;ISCiii PIE14/00031,No.CIBERehdISCiii;Severo Ochoa Excellence Accreditation,No.SEV-2016-0644)(Mato)

摘　　要：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 MATβwhich controls the activity of MATα2.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 MATα1.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.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,MAT1 A and MAT2 A, which encode for MATα1 and MATα2, the catalytic subunits of the MAT isoenzymes, respectively. A third gene MAT2 B, encodes a regulatory subunit known as MATβ which controls the activity of MATα2.MAT1 A, which is mainly expressed in hepatocytes, maintains the differentiated state of these cells, whilst MAT2 A and MAT2 B 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 MATα1. A switch from MAT1 A to MAT2 A/MAT2 B 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 Mat1 a-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.

关 键 词：METHIONINE adenosyltransferases S-ADENOSYLMETHIONINE Liver cancer HEPATOCELLULAR carcinoma CHOLANGIOCARCINOMA Biomarkers THERAPEUTIC targets 

分 类 号：R[医药卫生]