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.

• Authors: Huasong Lu, Yuhua Xue, Yuahua Xue, Guoying K Yu, Carolina Arias, Julie Lin, Susan Fong, Michel Faure, Ben Weisburd, Xiaodan Ji, Alexandre Mercier, James Sutton, Kunxin Luo, Zhenhai Gao, Qiang Zhou
• Journal: eLife (Elife) Vol. 4 Pg. e06535 (Jun 17 2015) ISSN: 2050-084X [Electronic] England
• PMID: 26083714 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• BRD4 protein, human
• Cell Cycle Proteins
• MYC protein, human
• Nuclear Proteins
• Proto-Oncogene Proteins c-myc
• Transcription Factors
• Positive Transcriptional Elongation Factor B
• CDK9 protein, human
• Cyclin-Dependent Kinase 9

Topics

• Cell Cycle Proteins
• Cyclin-Dependent Kinase 9 (antagonists & inhibitors, metabolism)
• Gene Expression Regulation
• Humans
• Nuclear Proteins (metabolism)
• Positive Transcriptional Elongation Factor B (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Transcription Factors (metabolism)