title: Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis.
abstract: Downregulation of liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and upregulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Being inhibited by its reaction product, MATII isoform upregulation cannot compensate for MATI/III decrease. Therefore, MAT1A:MAT2A switch contributes to decrease in SAM level in rodent and human hepatocarcinogenesis. SAM administration to carcinogen-treated rats prevents hepatocarcinogenesis, whereas MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development. This review focuses upon the pleiotropic changes, induced by MAT1A/MAT2A switch, associated with HCC development. Epigenetic control of MATs expression occurs at transcriptional and post-transcriptional levels. In HCC cells, MAT1A/MAT2A switch is associated with global DNA hypomethylation, decrease in DNA repair, genomic instability, and signaling deregulation including c-MYC overexpression, rise in polyamine synthesis, upregulation of RAS/ERK, IKK/NF-kB, PI3K/AKT, and LKB1/AMPK axis. Furthermore, decrease in MAT1A expression and SAM levels results in increased HCC cell proliferation, cell survival, and microvascularization. All of these changes are reversed by SAM treatment in vivo or forced MAT1A overexpression or MAT2A inhibition in cultured HCC cells. In human HCC, MAT1A:MAT2A and MATI/III:MATII ratios correlate negatively with cell proliferation and genomic instability, and positively with apoptosis and global DNA methylation. This suggests that SAM decrease and MATs deregulation represent potential therapeutic targets for HCC. Finally, MATI/III:MATII ratio strongly predicts patients' survival length suggesting that MAT1A:MAT2A expression ratio is a putative prognostic marker for human HCC.
authors.affiliation: Department of Clinical and Experimental Medicine, Laboratory of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Frau
authors.forename: Francesco
authors.initials: F
authors.lastname: Feo
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011379:Prognosis; D000091402:Prohibitins; D051381:Rats; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008716:Methionine Adenosyltransferase
keywords: 5-methyltetrahydrofolate homocysteine methyltransferase; 5’-Methylthioadenosine phosphorylase; 5′-MTA; 5′-methylthioadenosine; AKT; AMP activated protein kinase; AMPK; AP; AP-1; APEX1; ASH; ASO; AUF1; AUrich RNA binding factor 1; B-cell cell/lymphoma 2; BAK; BAX; BCL2; BCL2 antagonist killer; BCL2-associated x protein; BHMT; CBS; CDC2; CDC28 protein kinase b1; CSK1; DN; DUSP1; EGR-1; ERK; Epigenetic regulation; FAS; FOXM1; GI; GNMT; GSH; HCC; HCC with better prognosis; HCC with poorer prognosis; HCCB; HCCP; HGF; HIF-1α; Hepatocarcinogenesis; Hu antigen R; HuR; IKK; JAK; JUN; Janus kinase; LDL; LKB1; MAFK; MAPK; MAT; MDD; MDM2; MTHF-HMT; Methionine adenosyltransferase; Mtap; NASH; NF-kB; NOS; ODC; PCNA; PFK-2; PH; PHB1; PI3K; PIAS1; PP2A; PRMT5; Prognosis; Progression; RAS guanyl releasing protein 3; RASGRP3; RBP; ROS; S-adenosylhomocysteine; S-adenosylmethionine; S-phase kinase-associated protein 2; SAH; SAH hydroxylase; SAHH; SAM; SAM dacarboxylase; SKP2; SL; SP1; STAT1; Sdc; Signal transduction; Smr; Sms; Spp1; TNFα; TSC1; TSC2; USP7; Ubiquitin-specific-processing protease 7; V-AKT murine thymoma viral oncogene homolog; V-JUN avian sarcoma virus 17 oncogene homolog; V-MAF avian musculoaponeurotic fibrosarcoma oncogene family, protein K; V-MYB avian myeloblastosis viral oncogene homolog-like 2; VLDL; XIAP; activator protein-1; alcoholic steatohepatitis; antisense oligonucleotide; apurinic/apyrimidinic; betaine-homocysteine methyltransferase; c-Mybl2; cell division cycle 2; cystathionine β-synthase; dual-specificity phosphatase 1; dysplastic nodule; early growth response protein-1; endonuclease redox effector APE1/REF-1/APEX1; extracellular signal-regulated kinase; forkhead box M1B; genomic instability; glycine N-methyltransferase; hamartin; hepatocellular carcinoma; hepatocyte growth factor; hypoxia-inducible factor 1, alpha subunit; inhibitor of apoptosis, x-linked; inhibitor of kappa light chain gene enhancer in B cells, kinase of; low density lipoproteins; mRNA-binding proteins; mTORC2; mammalian target of rapamycin complex; methionine adenosyltransferase; methyl deficient diet; mitogen-activated protein kinase; mouse double minute 2 homolog; nitric oxide synthase; non-alcoholic steatohepatitis; nuclear factor kB; ornithine decarboxylase; p90RSK; partial hepatectomy; phosphatadylinositol 3-kinase; phosphofructokinase 2; prohibitin 1; proliferating cell nuclear antigen; protein arginine methyltransferase 5; protein inhibitor of activated STAT1; protein phosphatase 2A; reactive oxygen species; reduced glutathione; ribosomal protein S6 kinase polypeptide 2; secreted phosphoprotein 1; serine/threonine protein kinase 11; signal transducer and activator of transcription; specificity protein 1; spermidine synthase; spermine synthase; surrounding liver; tuberin; tumor necrosis factor receptor superfamily, member 6; tumor necrosis factor α; very low density lipoproteins