S-Adenosylmethionine Metabolism in Liver Cancer

Liver cancer is characterised by profound alterations in the methionine cycle, the principal source of the methyl donor S-adenosylmethionine (SAM). Under normal conditions, hepatocytes express methionine adenosyltransferase-1A (MAT1A) to sustain differentiated function and maintain SAM homeostasis. In hepatocellular carcinoma (HCC), MAT1A expression is often diminished while MAT2A and its regulatory partner MAT2B are induced, shifting SAM synthesis kinetics and supporting proliferative, migratory and anti-apoptotic phenotypes. SAM depletion impairs DNA, RNA and histone methylation, aggravating genomic instability, oxidative stress and aberrant signalling. Conversely, excessive SAM accumulation can trigger feedback inhibition of methylation pathways, disrupt trans-sulphuration and provoke lipid metabolic derangements, contributing to steatosis and tumour progression. Post-translational modifications, subcellular redistribution of MAT isoforms and accessory regulatory proteins further tune SAM availability. These changes present both biomarkers and therapeutic nodes: modulation of MAT activity, restoration of SAM levels and exploitation of synthetic lethality in MTAP-deleted tumours exemplify emerging strategies. Integrating multi-omic insights with structural and mechanistic studies is refining our understanding of SAM dynamics in liver carcinogenesis, with global relevance for diagnosis and targeted treatment.

Research from Nature Portfolio

Recent work has elucidated how post-translational regulation of MATIIα influences liver tumour growth. Acetylation at a conserved lysine residue leads to MATIIα destabilisation via enhanced ubiquitylation and proteasomal degradation, while deacetylation by histone deacetylase 3 stabilises the enzyme. Folate deprivation increases acetylation to moderate proliferation, and a single-site mutation reverses this effect. Critically, reduced acetylation levels have been observed in human hepatocellular carcinoma specimens, directly linking MATIIα turnover to tumour development and uncovering a regulatory axis that controls SAM production and cell proliferation.

S-Adenosylmethionine Metabolism in Liver Cancer publication trend

The graph below shows the total number of articles in s-adenosylmethionine metabolism in liver cancer across all publications each year (not limited to Nature Index journals).

Technical terms

S-adenosylmethionine (SAM): The universal methyl donor derived from methionine and ATP, essential for methylation reactions in DNA, RNA, proteins and lipids.

Methionine adenosyltransferase (MAT): Enzymes (isoforms MAT1A, MAT2A, MAT2B) that catalyse SAM synthesis, with distinct tissue distributions and regulatory properties.

One-carbon metabolism: A network of folate-dependent pathways that transfer single-carbon units for biosynthesis of nucleotides, amino acids and methylation reactions.

Trans-sulphuration pathway: A route whereby homocysteine is converted into cysteine and glutathione, linking methylation status to redox balance.

Acetylation and ubiquitylation: Post-translational modifications altering protein stability and activity; acetylation can promote ubiquitylation and proteasomal degradation.

References

1. Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer. Nature Communications (2015).
2. Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition. Archives of Toxicology (2024).
3. Translocation of Methionine Adenosyl Transferase MAT2A and Its Prognostic Relevance for Liver Hepatocellular Carcinoma. International Journal of Molecular Sciences (2023).
4. Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy. Experimental Biology and Medicine (2017).
5. SCR‐7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S‐adenosylmethionine‐competitive or the methylthioadenosine‐cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase‐deleted tumors. MedComm (2024).