Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
27793648
DOI
10.1016/j.yexcr.2016.10.018
PII: S0014-4827(16)30345-7
Knihovny.cz E-resources
- Keywords
- C-MYC, GLUT1, Glycolysis, Hippo, TEAD1, YAP1,
- MeSH
- Adaptor Proteins, Signal Transducing drug effects MeSH
- Apoptosis drug effects genetics MeSH
- DNA-Binding Proteins drug effects MeSH
- Phosphoproteins drug effects metabolism MeSH
- Genes, myc drug effects MeSH
- Hepatocyte Growth Factor MeSH
- Nuclear Proteins drug effects MeSH
- Humans MeSH
- Naphthoquinones pharmacology MeSH
- Glucose Transporter Type 1 metabolism MeSH
- Cell Proliferation drug effects genetics MeSH
- Proto-Oncogene Proteins drug effects MeSH
- YAP-Signaling Proteins MeSH
- Signal Transduction drug effects physiology MeSH
- TEA Domain Transcription Factors MeSH
- Transcription Factors drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Adaptor Proteins, Signal Transducing MeSH
- DNA-Binding Proteins MeSH
- Phosphoproteins MeSH
- Hepatocyte Growth Factor MeSH
- Nuclear Proteins MeSH
- macrophage stimulating protein MeSH Browser
- Naphthoquinones MeSH
- Glucose Transporter Type 1 MeSH
- Proto-Oncogene Proteins MeSH
- shikonin MeSH Browser
- YAP-Signaling Proteins MeSH
- SLC2A1 protein, human MeSH Browser
- TEAD1 protein, human MeSH Browser
- TEA Domain Transcription Factors MeSH
- Transcription Factors MeSH
- YAP1 protein, human MeSH Browser
The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear. In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism. We have found that two key regulators of glycolysis, C-MYC and GLUT1, are targets of the Hippo signaling pathway in human leukemia cells. Our results revealed that activation of MST1 by the natural compound shikonin inhibited the expression of GLUT1 and C-MYC. Furthermore, RNAi experiments confirmed the regulation of GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis. Surprisingly, YAP1 was found to positively regulate C-MYC mRNA levels in complex with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Hence, YAP1 serves as a rheostat for C-MYC, which is regulated by MST1. In addition, depletion of MST1 stimulates lactate production, whereas the specific depletion of TEAD1 has an opposite effect. The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. Finally, a bioinformatic analysis revealed conserved TEAD-binding motifs in the C-MYC and GLUT1 promoters providing another molecular data supporting our observations. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway.
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