WJG World Journal of Gastroenterology Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2019 August 21; 25(31): 4300-4319 DOI: 10.3748/wjg.v25.i31.4300 ISSN 1007-9327 (print) ISSN 2219-2840 (online) REVIEW Methionine adenosyltransferases in liver cancer Ben Murray, Lucia Barbier-Torres, Wei Fan, José M Mato, Shelly C Lu ORCID number: Ben Murray (0000-0001-5375-2124); Lucia Barbier-Torres (0000-0002-7675-2888); Wei Fan (0000-0001-6462-7425); Jose M Mato (0000-0003-1264-3153); Shelly C Lu (0000-0003-2128-5407). 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, 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 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 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. Key words: Methionine adenosyltransferases; S-adenosylmethionine; Liver cancer; Hepatocellular carcinoma; Cholangiocarcinoma; Biomarkers; Therapeutic targets WJG https://www.wjgnet.com August 21, 2019 Volume 25 Issue 31 4300