Abstract
The major biological methyl donor, S-adenosylmethionine (adoMet) synthesis occurs mainly in the liver. Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are two key enzymes involved in the functional implications of that variation. We collected 42 RNA-seq data from paired hepatocellular carcinoma (HCC) and its adjacent normal liver tissue from the Cancer Genome Atlas (TCGA). There was no mutation found in MAT1A or GNMT RNA in the 42 HCC patients. The 11,799 genes were annotated in the RNA-Seq data, and their expression levels were used to investigate the phenotypes of low MAT1A and low GNMT by Gene Set Enrichment Analysis (GSEA). The REACTOME_TRANSLATION gene set was enriched and visualized in a heatmap along with corresponding differences in gene expression between low MAT1A versus high MAT1A and low GNMT versus high GNMT. We identified 43 genes of the REACTOME_TRANSLATION gene set that are powerful prognosis factors in HCC. The significantly predicted genes were referred into eukaryotic translation initiation (EIF3B, EIF3K), eukaryotic translation elongation (EEF1D), and ribosomal proteins (RPs). Cell models expressing various MAT1A and GNMT proved that simultaneous restoring the expression of MAT1A and GNMT decreased cell proliferation, invasion, as well as the REACTOME_TRANSLATION gene EEF1D, consistent with a better prognosis in human HCC. We demonstrated new findings that downregulation or defect in MAT1A and GNMT genes can enrich the protein-associated translation process that may account for poor HCC prognosis. This is the first study demonstrated that MAT1A and GNMT, the 2 key enzymes involved in methionine cycle, could attenuate the function of ribosome translation. We propose a potential novel mechanism by which the diminished GNMT and MAT1A expression may confer poor prognosis for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and incidence of about 10.1 cases per 100,000 persons, and HCC is ranked as the sixth most common neoplasm and the third leading cause of cancer death [1]
Based on the above data, we explored the data from 42 paired HCC tumor and adjacent normal tissues collected from the Cancer RNA-Seq Nexus [29], and identified the adjacent normal tissues collected from the Cancer RNA-Seq Nexus [29], and identified enriched pathways associated with defected Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) expression
eukaryotic translation elongation factor 1 delta (EEF1D) expression was found to have a strongly inverse correlation with cell doubling time (R= −0.834, p = 0.010) (Figure 4E). These results indicated that EEF1D may play a significant role in HCC progression independent of protein translation, and MAT1A, GNMT and MAT2A may modulate HCC proliferation/and or progression through the expression of REATOME gene EEF1D
Summary
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and incidence of about 10.1 cases per 100,000 persons, and HCC is ranked as the sixth most common neoplasm and the third leading cause of cancer death [1]. MAT and GNMT genes are commonly diminished in human HCC and hepatoma cell lines [15,16,17,18,19]. Deletion of gnmt promotes the susceptibility to liver cancer in mice [22]; gnmt knockout mice exhibited elevated hepatic adoMet levels and S-adenosylhomocysteine hydrolase (SAHH) expression in the liver [22]. These studies suggested that defective MAT and/or GNMT proteins could be early markers in human HCC development
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