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

被引：165

作者：

Huang, Chun-Hao ^{[1
,2
,3
]}

Lujambio, Amaia ^{[1
,3
]}

Zuber, Johannes ^{[3
,4
]}

Tschaharganeh, Darius F. ^{[1
]}

Doran, Michael G. ^{[1
]}

Evans, Michael J. ^{[1
]}

Kitzing, Thomas ^{[1
,3
]}

Zhu, Nan ^{[1
]}

de Stanchina, Elisa ^{[1
]}

Sawyers, Charles L. ^{[1
,5
]}

Armstrong, Scott A. ^{[1
]}

Lewis, Jason S. ^{[1
]}

Sherr, Charles J. ^{[6
]}

Lowe, Scott W. ^{[1
,2
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[2] Cornell Univ, Weill Grad Sch Med Sci, Cell & Dev Biol Program, New York, NY 10065 USA

[3] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[4] Res Inst Mol Pathol, A-1030 Vienna, Austria

[5] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

[6] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA

来源：

GENES & DEVELOPMENT | 2014年 / 28卷 / 16期

关键词：

RNAi screen; CDK9; MYC; oncogene addiction; transcription elongation; DEPENDENT KINASE INHIBITOR; C-MYC; CELLULAR PROLIFERATION; LUNG-CANCER; P-TEFB; GENES; EXPRESSION; TARGET; ACTIVATION; INITIATION;

D O I：

10.1101/gad.244368.114

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1800 / 1814

页数：15

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