Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 17, 2015
- Source ID
- 10.7554/elife.06535
Entities
People
- Alexandre Mercier
- Ben Weisburd
- Carolina Arias
- Guoying K Yu
- Huasong Lu
- James Sutton
- Julie Lin
- Kunxin Luo
- Michel Faure
- Qiang Zhou
- Susan Fong
- Xiaodan Ji
- Yuhua Xue
- Zhenhai Gao
Organizations
- National Institutes of Health
- National Natural Science Foundation of China
- United States Department of Defense
- Xiamen University