Article Abstract

Deregulation of methionine metabolism as determinant of progression and prognosis of hepatocellular carcinoma

Authors: Rosa M. Pascale, Claudio F. Feo, Diego F. Calvisi, Francesco Feo

Abstract

The under-regulation of liver-specific MAT1A gene codifying for S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and the up-regulation of widely expressed MAT2A, MATII isozyme occurs in hepatocellular carcinoma (HCC). MATα1:MATα2 switch strongly contributes to the fall in SAM liver content both in rodent and human liver carcinogenesis. SAM administration to carcinogen-treated animals inhibits hepatocarcinogenesis. The opposite occurs in Mat1a-KO mice, in which chronic SAM deficiency is followed by HCC development. This review focuses upon the changes, induced by the MATα1:MATα2 switch, involved in HCC development. In association with MATα1:MATα2 switch there occurs, in HCC, global DNA hypomethylation, decline of DNA repair, genomic instability, and deregulation of different signaling pathways such as overexpression of c-MYC (avian myelocytomatosis viral oncogene homolog), increase of polyamine (PA) synthesis and RAS/ERK (Harvey murine sarcoma virus oncogene homolog/extracellular signal-regulated kinase), IKK/NF-kB (I-k kinase beta/nuclear factor kB), PI3K/AKT, and LKB1/AMPK axes. Furthermore, a decrease in MATα1 expression and SAM level induces HCC cell proliferation and survival. SAM treatment in vivo and enforced MATα1 overexpression or MATα2 inhibition, in cultured HCC cells, prevent these changes. A negative correlation of MATα1:MATα2 and MATI/III:MATII ratios with cell proliferation and genomic instability and a positive correlation with apoptosis and global DNA methylation are present in human HCC. Altogether, these data suggest that the decrease of SAM level and the deregulation of MATs are potential therapeutic targets for HCC.