Brd4-dependent CDK9 expression induction upon sustained pharmacological inhibition of P-TEFb kinase activity

CDK9 is the kinase subunit of P-TEFb (positive transcription elongation factor b), which is crucial for effective transcriptional elongation. The activity of P-TEFb is well maintained, mainly through dynamic association with several larger protein complexes. Here, we show that CDK9 expression is induced upon inhibition of P-TEFb activity, a process dependent on Brd4 as later revealed. Brd4 inhibition synergizes with CDK9 inhibitor to suppress P-TEFb activity and tumor cell growth. Our study suggests that com-bined inhibition of Brd4 and CDK9 can be evaluated as a potential therapeutic strategy.& COPY; 2023 Elsevier Inc. All rights reserved.

Automated summary

CDK9 is a crucial kinase subunit of P-TEFb that is important for effective transcriptional elongation. The activity of P-TEFb is maintained through dynamic association with larger protein complexes. In this study, we find that CDK9 expression is induced upon inhibition of P-TEFb activity, a process dependent on Brd4. Inhibition of Brd4 synergizes with CDK9 inhibitor to suppress P-TEFb activity and tumor cell growth. Our findings suggest that combined inhibition of Brd4 and CDK9 could be a potential therapeutic strategy.