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Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism

2015; eLife Sciences Publications Ltd; Volume: 4; Linguagem: Inglês

10.7554/elife.06535

2050-084X

Huasong Lu, Yuhua Xue, Guoying Karen Yu, Carolina Arias, Julie Lin, Susan Fong, Michel Faure, Ben Weisburd, Xiao‐Dan Ji, Alexandre Mercier, James Sutton, Kunxin Luo, Zhenhai Gao, Qiang Zhou,

Ubiquitin and proteasome pathways

CDK9 is the kinase subunit of positive transcription elongation factor b (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.