CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma
- Chun-Hao Huang1,2,3,7,
- Amaia Lujambio1,3,7,
- Johannes Zuber3,4,
- Darjus F. Tschaharganeh1,
- Michael G. Doran1,
- Michael J. Evans1,
- Thomas Kitzing1,3,
- Nan Zhu1,
- Elisa de Stanchina1,
- Charles L. Sawyers1,5,
- Scott A. Armstrong1,
- Jason S. Lewis1,
- Charles J. Sherr6 and
- Scott W. Lowe1,2,3,5
- 1Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
- 2Cell and Developmental Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10065, USA;
- 3Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- 4Research Institute of Molecular Pathology, Vienna, 1030, Austria;
- 5Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
- 6Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
- Corresponding author: lowes{at}mskcc.org
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↵7 These authors contributed equally to this work.
Abstract
One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.244368.114.
- Received April 28, 2014.
- Accepted July 21, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
