CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

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...

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Published inGenes & development Vol. 28; no. 16; pp. 1800 - 1814
Main Authors Huang, Chun-Hao, Lujambio, Amaia, Zuber, Johannes, Tschaharganeh, Darjus F, Doran, Michael G, Evans, Michael J, Kitzing, Thomas, Zhu, Nan, de Stanchina, Elisa, Sawyers, Charles L, Armstrong, Scott A, Lewis, Jason S, Sherr, Charles J, Lowe, Scott W
Format Journal Article
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 15.08.2014
Subjects
Animals
Carcinoma, Hepatocellular - enzymology
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase 9 - metabolism
Female
Gene Expression
Gene Library
Hep G2 Cells
Humans
Liver Neoplasms - enzymology
Liver Neoplasms - genetics
Liver Neoplasms - pathology
Mice
Positive Transcriptional Elongation Factor B - genetics
Positive Transcriptional Elongation Factor B - metabolism
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Research Paper
RNA Interference
RNA, Small Interfering - metabolism
Transcription Elongation, Genetic - physiology
CDK9
transcription elongation
oncogene addiction
RNAi screen
MYC
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Summary: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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These authors contributed equally to this work.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.244368.114