CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

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.

VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells

“…In addition to promoting cell-cycle arrest through CKI inhibition, both flavopiridol and roscovitine can stabilize p53 by inhibiting CDK9-mediated elongation of transcripts encoding MDM2 and MDM4, which normally contribute to p53 degradation (Lu et al, 2001;St etková et al, 2020). Stabilization of p53 in this setting then contributes to cell-cycle arrest by inducing expression of CDKIs, such as p21.…”

Genome-wide identification of cyclin-dependent kinase (CDK) genes affecting adipocyte differentiation in cattle

“…The CDK gene family and the interacting genes formed an integrated network as shown by literature mining using the Agilent Literature Search plug-in of Cytoscape (Additional file 7 ) [ 38 ]. For example, CDK7 could directly activate CDK9 to maintain a high expression of MDM4 and MDM2 [ 36 , 37 ]. MDM2 facilitates adipocyte differentiation through CRTC-mediated activation of STAT3 [ 39 ].…”

A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches

“…Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation [33]. Previous studies reported that activity of CDK9 was involved in maintaining a high expression level of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4 [34]. Moreover, CDK9 is a promising prognostic marker and therapeutic target in cancers [35], including activity castration-resistant prostate cancers (CRPCs) models [36].…”