Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism
- University of California, Berkeley, United States
- Xiamen University, China
- Novartis Institute for BioMedical Research, United States
Abstract
CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.
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© 2015, Lu et al.
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Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism
eLife 4:e06535.
https://doi.org/10.7554/eLife.06535
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