2. Academic Validation
  3. CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

  • Cell Death Dis. 2020 Sep 15;11(9):754. doi: 10.1038/s41419-020-02971-3.
Monika Štětková 1,  Kateřina Growková 1,  Petr Fojtík 1 2,  Barbora Valčíková 1 2,  Veronika Palušová 1 2,  Amandine Verlande 1 2,  Radek Jorda 3 4,  Vladimír Kryštof 3 4,  Václav Hejret 5,  Panagiotis Alexiou 5,  Vladimír Rotrekl 1 2,  Stjepan Uldrijan 6 7
Affiliations

Affiliations

  • 1 Faculty of Medicine, Department of Biology, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
  • 2 International Clinical Research Center, St. Anne's University Hospital, Pekařská 53, 656 91, Brno, Czech Republic.
  • 3 Laboratory of Growth Regulators, Palacký University and Institute of Experimental Botany, The Czech Academy of Sciences, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
  • 4 Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacký University, Hněvotínská 5, 779 00, Olomouc, Czech Republic.
  • 5 Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
  • 6 Faculty of Medicine, Department of Biology, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic. uldrijan@med.muni.cz.
  • 7 International Clinical Research Center, St. Anne's University Hospital, Pekařská 53, 656 91, Brno, Czech Republic. uldrijan@med.muni.cz.
PMID: 32934219 DOI: 10.1038/s41419-020-02971-3
Abstract

The identification of the essential role of cyclin-dependent kinases (CDKs) in the control of cell division has prompted the development of small-molecule CDK inhibitors as Anticancer drugs. For many of these compounds, the precise mechanism of action in individual tumor types remains unclear as they simultaneously target different classes of CDKs - Enzymes controlling the cell cycle progression as well as CDKs involved in the regulation of transcription. CDK inhibitors are also capable of activating p53 tumor suppressor in tumor cells retaining wild-type p53 gene by modulating MDM2 levels and activity. In the current study, we link, for the first time, CDK activity to the overexpression of the MDM4 (MDMX) oncogene in Cancer cells. Small-molecule drugs targeting the CDK9 kinase, dinaciclib, flavopiridol, roscovitine, AT-7519, SNS-032, and DRB, diminished MDM4 levels and activated p53 in A375 melanoma and MCF7 breast carcinoma cells with only a limited effect on MDM2. These results suggest that MDM4, rather than MDM2, could be the primary transcriptional target of pharmacological CDK inhibitors in the p53 pathway. CDK9 Inhibitor atuveciclib downregulated MDM4 and enhanced p53 activity induced by nutlin-3a, an inhibitor of p53-MDM2 interaction, and synergized with nutlin-3a in killing A375 melanoma cells. Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4.

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