Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2019; 25(31): 4300-4319
Published online Aug 21, 2019. doi: 10.3748/wjg.v25.i31.4300
Methionine adenosyltransferases in liver cancer
Ben Murray, Lucia Barbier-Torres, Wei Fan, José M Mato, Shelly C Lu
Ben Murray, Lucia Barbier-Torres, Wei Fan, Shelly C Lu, Division of Digestive and Liver diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
José M Mato, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Derio 48160, Bizkaia, Spain
Author contributions: Ben Murray and Lucia Barbier-Torres contributed equally in reviewing the literature and drafting of the manuscript. Wei Fan assisted in literature review and drafting of the manuscript. José M Mato provided critical reading of the manuscript. Shelly C Lu provided critical editing and revision of the manuscript. All authors approved the final version of the manuscript.
Supported by 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. CIBERehd-ISCiii; and Severo Ochoa Excellence Accreditation, No. SEV-2016-0644) (Mato).
Conflict-of-interest statement: None of the authors have any conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Shelly C Lu, MD, Professor, Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Davis Building, Room No. 2097, 8700 Beverly Blvd., Los Angeles, CA, 90048, United States. shelly.lu@cshs.org
Telephone: +1-310-4235692 Fax: +1-310-4230653
Received: April 13, 2019
Peer-review started: April 15, 2019
First decision: May 16, 2019
Revised: May 31, 2019
Accepted: July 19, 2019
Article in press: July 19, 2019
Published online: August 21, 2019
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 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 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.

Keywords: Methionine adenosyltransferases, S-adenosylmethionine, Liver cancer, Hepatocellular carcinoma, Cholangiocarcinoma, Biomarkers, Therapeutic targets

Core tip: In this review we provide the most comprehensive guide to methionine adenosyltransferases discussing their structures, functions and consequences of dysregulation in liver cancers emphasizing their potential as prognostic biomarkers for liver cancers and as targets for liver cancer therapy.