CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma.
CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma.
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DOI：
10.1101/gad.244368.114
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发表时间：
2014-08-15
影响因子：
10.5
通讯作者：
Lowe SW
中科院分区：
文献类型：
--
作者：
Huang CH;Lujambio A;Zuber J;Tschaharganeh DF;Doran MG;Evans MJ;Kitzing T;Zhu N;de Stanchina E;Sawyers CL;Armstrong SA;Lewis JS;Sherr CJ;Lowe SW
通过在基因定义的Myc驱动的肝细胞癌模型中筛选针对已知药物靶标的定制shRNA文库，Huang等人鉴定出Cdk9为疾病维持所需。药理学或shRNA介导的CDK9抑制导致与MYC表达水平相关的稳健的抗肿瘤作用，并且依赖于CDK9和MYC在转录延伸中发挥的作用。这项研究提出了CDK9抑制作为MYC过表达肝肿瘤的治疗策略，并强调了转录延长在癌细胞对MYC成瘾中的相关性。新诊断的肝细胞癌（HCC）的一年存活率<50%，并且由于其主要遗传驱动因素的侵袭性和不可治愈性，不可切除的HCC具有令人沮丧的预后。通过在基因定义的Myc驱动的HCC模型中筛选针对已知药物靶点的定制shRNA文库，我们确定了疾病维持所需的细胞周期蛋白依赖性激酶9（Cdk9）。药理学或shRNA介导的CDK9抑制导致与MYC表达水平相关的稳健的抗肿瘤作用，并且依赖于CDK9和MYC在转录延伸中发挥的作用。我们的研究结果确立了CDK9抑制作为MYC过表达肝肿瘤的治疗策略，并强调了转录延长在癌细胞对MYC成瘾中的相关性。
By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven hepatocellular carcinoma model, Huang et al. identified 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. This study proposes CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlights the relevance of transcription elongation in the addiction of cancer cells to MYC. 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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