The complex Post-transcriptional Regulation of Genes coding for Methionine Adenosyl Transferase: New insights for liver cancer.

Abstract

Methionine adenosyltransferases (MATs) catalyze the synthesis of S-adenosylmethionine (SAM), the universal methyl donor involved in methylation reactions, redox balance, and polyamine synthesis. In mammals, three MAT genes, MAT1A, MAT2A, and MAT2B, exhibit tissue-specific expression, with MAT1A predominating in healthy liver and MAT2A/MAT2B upregulated during liver injury and malignancy. A shift from MAT1A to MAT2A/MAT2B expression is a hallmark of hepatocellular carcinoma (HCC), contributing to decreased SAM levels and promoting tumorigenesis. Recent findings highlight the pivotal role of post-transcriptional regulation in controlling MAT gene expression. N6-methyladenosine (m6A) modification, the most prevalent internal mRNA modification, plays a dynamic role in determining the fate of MAT2A mRNA. m6A marks regulate MAT2A mRNA splicing and stability in response to stress and metabolic changes. Additionally, RNA-binding proteins (RBPs) such as ELAVL1 and hnRNPD bind to MAT mRNAs, modulating their stability and translation. Dysregulation of these RBPs in liver disease alters MAT expression profiles. Non-coding RNAs, including microRNAs such as miR-29, miR-21, and miR-485, and long non-coding RNAs such as LINC00662 and SNGH6, modulate MAT expression post-transcriptionally by targeting MAT transcripts directly or influencing RNA-binding proteins (RBPs) and m6A writers/readers. Together, these mechanisms form a complex and intricate post-transcriptional regulatory network that governs MAT activity in physiological and pathological states. This review examines emerging insights into MAT post-transcriptional regulation, focusing on its implications for liver cancer, and opens new avenues for developing therapies that target these regulatory mechanisms.