Deregulated 14-3-3 Zeta And Methionine Adenosyltransferase Alpha 1 Interplay Promotes Liver Cancer Tumorigenesis In Mice And Humans

Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MAT alpha 1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3 zeta. The MAT alpha 1/14-3-3 zeta complex was critical for the expression of 14-3-3 zeta. Similarly, the knockdown and small molecule inhibitor for 14-3-3 zeta (BV02), and ChIP analysis demonstrated the role of 14-3-3 zeta in suppressing MAT1A expression. Interaction between MAT alpha 1 and 14-3-3 zeta occurs directly and is enhanced by AKT2 phosphorylation of MAT alpha 1. Blocking their interaction enabled nuclear MAT alpha 1 translocation and inhibited tumorigenesis. In contrast, overexpressing 14-3-3 zeta lowered nuclear MAT alpha 1 levels and promoted tumor progression. However, tumor-promoting effects of 14-3-3 zeta were eliminated when liver cancer cells expressed mutant MAT alpha 1 unable to interact with 14-3-3 zeta. Taken together, the reciprocal negative regulation that MAT alpha 1 and 14-3-3 zeta exert is a key mechanism in liver tumorigenesis.