title: Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis.
abstract: 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.
authors: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic. Electronic address: karel.valis@biomed.cas.cz.
authors: Karel
authors: K
authors: Vališ
authors: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.
authors: Pavel
authors: P
authors: Talacko
authors: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.
authors: Valéria
authors: V
authors: Grobárová
authors: Faculty of Science, Charles University, Prague, Czech Republic.
authors: Jan
authors: J
authors: Černý
authors: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic. Electronic address: pnovak@biomed.cas.cz.
authors: Petr
authors: P
authors: Novák
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D017228:Hepatocyte Growth Factor; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000187:drug effects; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000187:drug effects; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D009285:Naphthoquinones; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C495677:SLC2A1 protein, human; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C082332:macrophage stimulating protein; C016101:shikonin; D017228:Hepatocyte Growth Factor
keywords: C-MYC; GLUT1; Glycolysis; Hippo; TEAD1; YAP1