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Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis
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SYSNO ASEP 0467979 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis Tvůrce(i) Vališ, Karel (MBU-M) ORCID
Talacko, Pavel (MBU-M)
Grobárová, Valeria (MBU-M)
Černý, J. (CZ)
Novák, Petr (MBU-M) RID, ORCIDZdroj.dok. Experimental Cell Research. - : Elsevier - ISSN 0014-4827
Roč. 349, č. 2 (2016), s. 273-281Poč.str. 9 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova Hippo ; Glycolysis ; C-MYC Vědní obor RIV EE - Mikrobiologie, virologie CEP GP14-21095P GA ČR - Grantová agentura ČR GA13-16565S GA ČR - Grantová agentura ČR LQ1604 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora MBU-M - RVO:61388971 UT WOS 000389163200008 EID SCOPUS 84997096217 DOI 10.1016/j.yexcr.2016.10.018 Anotace he 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.Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2017
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