1. Biochemistry and Chemical Biology
  2. Chromosomes and Gene Expression
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Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism

  1. Huasong Lu
  2. Yuahua Xue
  3. Guoying K Yu
  4. Carolina Arias
  5. Julie Lin
  6. Susan Fong
  7. Michel Faure
  8. Ben Weisburd
  9. Xiaodan Ji
  10. Alexandre Mercier
  11. James Sutton
  12. Kunxin Luo
  13. Zhenhai Gao
  14. Qiang Zhou  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Xiamen University, China
  3. Novartis Institute for BioMedical Research, United States
Research Article
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Cite this article as: eLife 2015;4:e06535 doi: 10.7554/eLife.06535

Abstract

CDK9 is the kinase subunit of 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.

Article and author information

Author details

  1. Huasong Lu

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yuahua Xue

    Innovation Center of Cell Signaling Network, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Guoying K Yu

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Carolina Arias

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Julie Lin

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Susan Fong

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Michel Faure

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ben Weisburd

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Xiaodan Ji

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alexandre Mercier

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. James Sutton

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kunxin Luo

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Zhenhai Gao

    Novartis Institute for BioMedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Qiang Zhou

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    qzhou@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Kevin Struhl, Harvard Medical School, United States

Publication history

  1. Received: January 18, 2015
  2. Accepted: June 16, 2015
  3. Accepted Manuscript published: June 17, 2015 (version 1)
  4. Version of Record published: July 3, 2015 (version 2)

Copyright

© 2015, Lu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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