TY - JOUR TI - Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism AU - Lu, Huasong AU - Xue, Yuhua AU - Yu, Guoying K AU - Arias, Carolina AU - Lin, Julie AU - Fong, Susan AU - Faure, Michel AU - Weisburd, Ben AU - Ji, Xiaodan AU - Mercier, Alexandre AU - Sutton, James AU - Luo, Kunxin AU - Gao, Zhenhai AU - Zhou, Qiang A2 - Struhl, Kevin VL - 4 PY - 2015 DA - 2015/06/17 SP - e06535 C1 - eLife 2015;4:e06535 DO - 10.7554/eLife.06535 UR - https://doi.org/10.7554/eLife.06535 AB - 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. KW - MYC KW - CDK9 KW - BRD4 KW - CDK9 inhibitor KW - RNA polymerase pause and release KW - transcriptional elongation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -