Deregulated 14-3-3ζ and methionine adenosyltransferase α1 interplay promotes liver cancer tumorigenesis in mice and humans
| Autor: | Wei Fan, Ting Liu, Yuan Li, Ekihiro Seki, Liqing Lu, Shelly C. Lu, Michitaka Matsuda, Tony W.H. Li, Neil A. Bhowmick, Heping Yang, José M. Mato, Jing Zhang, Maria Lauda Tomasi, Lucía Barbier-Torres, Jiaohong Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Liver Cancer
Cancer Research Carcinoma Hepatocellular Carcinogenesis Chronic Liver Disease and Cirrhosis Clinical Sciences Oncology and Carcinogenesis AKT2 Biology Cell Transformation medicine.disease_cause Interactome Article Mice Rare Diseases Genetics medicine 2.1 Biological and endogenous factors Animals Humans Oncology & Carcinogenesis Aetiology Molecular Biology Cancer Neoplastic Gene knockdown Liver Disease Carcinoma Liver Neoplasms Hepatocellular Methionine Adenosyltransferase medicine.disease Cell Transformation Neoplastic 14-3-3 Proteins Tumor progression Cancer research Phosphorylation Digestive Diseases Liver cancer |
| Zdroj: | Oncogene Oncogene, vol 40, iss 39 |
| Popis: | Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MATα1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3ζ. The MATα1/14-3-3ζ complex was critical for the expression of 14-3-3ζ. Similarly, the knockdown and small molecule inhibitor for 14-3-3ζ (BV02), and ChIP analysis demonstrated the role of 14-3-3ζ in suppressing MAT1A expression. Interaction between MATα1 and 14-3-3ζ occurs directly and is enhanced by AKT2 phosphorylation of MATα1. Blocking their interaction enabled nuclear MATα1 translocation and inhibited tumorigenesis. In contrast, overexpressing 14-3-3ζ lowered nuclear MATα1 levels and promoted tumor progression. However, tumor-promoting effects of 14-3-3ζ were eliminated when liver cancer cells expressed mutant MATα1 unable to interact with 14-3-3ζ. Taken together, the reciprocal negative regulation that MATα1 and 14-3-3ζ exert is a key mechanism in liver tumorigenesis. |
| Databáze: | OpenAIRE |
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