S-Adenosylmethionine Inhibits La Ribonucleoprotein Domain Family Member 1 in Murine Liver and Human Liver Cancer Cells.

BACKGROUND & AIMS Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion, develop non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, the phosphos-proteome has not been characterized and whether they contribute to liver pathology is largely unknown. Our study aimed to fill this gap. APPROACH & RESULTS We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found the most striking change was hyperphosphorylation and increased content of La-Related Protein 1 (LARP1), which in the unphosphorylated form negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in the KO livers. The translation of TOP mRNAs RPS3 and RPL18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a novel, SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1 overexpression mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC. CONCLUSION Our results reveal a novel SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.