Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy

Abstract

Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes' role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein-protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT's tumorigenic role in identifying future targets for cancer therapy.

Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics

“…Among the essential translocators, we identified the S-adenosylmethionine synthase MAT2A, which is involved in the synthesis of S-Adenosyl-Methionine, a major methyl donor. Methylation is a well-established epigenetic mark and suspected to be highly correlated to the etiology of hepatocellular carcinoma amongst other cancers (11). We show for the first time that nuclear localization of MAT2A is cell cycle dependent in proliferating cells.…”

The biological functions of target genes in pan-cancers and cell lines were predicted by miR-375 microarray data from GEO database and bioinformatics

“…MAT2B can induce the growth and survival of cancer cells, enhance tumor migration and play a carcinogenic role. The increased expression of MAT2B happens in human liver, colon, gastric, breast, pancreas and prostate cancer [ 67 ]. In addition to interacting with MAT II, the mutations of MAT2B can interact with other else proteins, for example, including HuR [ 68 ].…”

Thyroid Tumor: Investigating MicroRNA-21 Gene Suppression in FTC and FTA

“… 19 While few studies have investigated TIMP3 in FTC and FTA, it has been reported to be downregulated in papillary thyroid cancer (PTC) but expressed in normal thyroid tissues. 19 In a study of TIMP3 regulation of migration, invasion, and in vivo tumorigenicity of thyroid tumor cells, Borrello et al 20 found that TIMP3 induced reduced metastatic activities of human thyroid cell line NIM1 by repressing angiogenesis and macrophage infiltration in PTC-derived NIM1 cell line, indicating that TIMP3 is involved in a negative regulatory role. 19 MAT2A mRNA level is post-transcriptionally regulated by methylated-HuR and non-methylated-HuR.…”

“… 30 From the results of the study, metalloproteinase-3 (TIMP3) gene was found to be downregulated in both FTC and FTA. TIMP3 have been previously reported to be downregulated in primary thyrocytes infected with RET/PTC1 retroviral vector 20 and hypermethylated in association with BRAF mutation. 31 Hypermethylation of TIMP3 leads to silenced expression and agrees with similar findings on papillary thyroid carcinoma (PTC)-derived tumor cell lines which reported increased reversal upon treatment with a demethylating agent (5-Aza-dC).…”