title: 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.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Huasong
authors.initials: H
authors.lastname: Lu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Innovation Center of Cell Signaling Network, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
authors.forename: Yuahua
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Guoying K
authors.initials: GK
authors.lastname: Yu
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Carolina
authors.initials: C
authors.lastname: Arias
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Lin
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Fong
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Michel
authors.initials: M
authors.lastname: Faure
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Ben
authors.initials: B
authors.lastname: Weisburd
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Ji
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mercier
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: James
authors.initials: J
authors.lastname: Sutton
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Kunxin
authors.initials: K
authors.lastname: Luo
authors.affiliation: Novartis Institute for BioMedical Research, Emeryville, United States.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D018797:Cell Cycle Proteins; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D042863:Cyclin-Dependent Kinase 9; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human; C467969:CDK9 protein, human
keywords: BRD4; CDK9; CDK9 inhibitor; MYC; RNA polymerase pause and release; biochemistry; chromosomes; genes; human; transcriptional elongation