Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression.
Down-regulation of the liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and up-regulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Here we found Mat1A:Mat2A switch and low SAM levels, associated with CpG hypermethylation and histone H4 deacetylation of Mat1A promoter, and prevalent CpG hypomethylation and histone H4 acetylation in Mat2A promoter of fast-growing HCC of F344 rats, genetically susceptible to hepatocarcinogenesis. In HCC of genetically resistant BN rats, very low changes in the Mat1A:Mat2A ratio, CpG methylation, and histone H4 acetylation occurred. The highest MAT1A promoter hypermethylation and MAT2A promoter hypomethylation occurred in human HCC with poorer prognosis. Furthermore, levels of AUF1 protein, which destabilizes MAT1A messenger RNA (mRNA), Mat1A-AUF1 ribonucleoprotein, HuR protein, which stabilizes MAT2A mRNA, and Mat2A-HuR ribonucleoprotein sharply increased in F344 and human HCC, and underwent low/no increase in BN HCC. In human HCC, Mat1A:MAT2A expression and MATI/III:MATII activity ratios correlated negatively with cell proliferation and genomic instability, and positively with apoptosis and DNA methylation. Noticeably, the MATI/III:MATII ratio strongly predicted patient survival length. Forced MAT1A overexpression in HepG2 and HuH7 cells led to a rise in the SAM level, decreased cell proliferation, increased apoptosis, down-regulation of Cyclin D1, E2F1, IKK, NF-κB, and antiapoptotic BCL2 and XIAP genes, and up-regulation of BAX and BAK proapoptotic genes. In conclusion, we found for the first time a post-transcriptional regulation of MAT1A and MAT2A by AUF1 and HuR in HCC. Low MATI/III:MATII ratio is a prognostic marker that contributes to determine a phenotype susceptible to HCC and patients' survival.


CONCLUSIONS
Interference with cell cycle progression and I-kappa B kinase (IKK)/nuclear factor kappa B (NF-κB) signaling contributes to the antiproliferative and proapoptotic effect of high SAM levels in HCC.
Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
Maddalena
M
Frau
Maria L
ML
Tomasi
Maria M
MM
Simile
Maria I
MI
Demartis
Fabiana
F
Salis
Gavinella
G
Latte
Diego F
DF
Calvisi
Maria A
MA
Seddaiu
Lucia
L
Daino
Claudio F
CF
Feo
Stefania
S
Brozzetti
Giuliana
G
Solinas
Satoshi
S
Yamashita
Toshikazu
T
Ushijima
Francesco
F
Feo
Rosa M
RM
Pascale
D000818:Animals; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D019175:DNA Methylation; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008716:Methionine Adenosyltransferase / Q000235:genetics* / Q000378:metabolism; D015999:Multivariate Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D012436:S-Adenosylmethionine / Q000378:metabolism; D018709:Statistics, Nonparametric; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D012436:S-Adenosylmethionine; C506577:MAT1A protein, human; C512846:Mat2a protein, rat; D008716:Methionine Adenosyltransferase