[EEF1A2 inhibits the p53 function in hepatocellular carcinoma via PI3K/AKT/mTOR-dependent stabilization of MDM4].
Upregulation of mouse double minute 4 (MDM4) is a frequent event in human hepatocellular carcinoma (HCC) but the underlying molecular mechanisms are poorly characterized. In this study a potential role of the phosphoinositide-3-kinase/v-AKT murine thymoma viral oncogene homolog/mammalian target of rapamycin (PI3K/AKT/mTOR) cascade was investigated in the regulation of MDM4 in HCC. Inhibition of the PI3K-AKT and/or mTOR pathways lowered MDM4 protein levels in HCC cells. Mechanistic protection from proteasomal degradation resulted from de-ubiquitination by ubiquitin-specific protease 2a and AKT-mediated phosphorylation of MDM4, thus increasing MDM4 protein levels. These findings were corroborated in a chimeric AKT mouse model. Upregulation of PI3K/AKT/mTOR signaling may result from overexpression of the eukaryotic elongation factor 1A2 (EEF1A2). Finally, a strong association between the expression of EEF1A2, phosphorylated AKT and MDM4 was observed in human HCC samples. Strong activation of the EEF1A2/PI3K/AKT/mTOR/MDM4 signaling pathway was observed in HCC patients with short survival suggesting that targeting this axis might be a promising approach in a subset of HCC patients.
Pathologisches Institut, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Deutschland, thomas.longerich@med.uni-heidelberg.de.
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D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D020648:Peptide Elongation Factor 1 / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D020648:Peptide Elongation Factor 1; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C503234:EEF1A2 protein, human; C482775:MDM4 protein, human