Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.
Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.
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DOI：
10.1016/j.cell.2018.09.051
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发表时间：
2018-11-15
期刊：
影响因子：
64.5
通讯作者：
Issa JJ
中科院分区：
文献类型：
--
作者：
Zhang H;Pandey S;Travers M;Sun H;Morton G;Madzo J;Chung W;Khowsathit J;Perez-Leal O;Barrero CA;Merali C;Okamoto Y;Sato T;Pan J;Garriga J;Bhanu NV;Simithy J;Patel B;Huang J;Raynal NJ;Garcia BA;Jacobson MA;Kadoch C;Merali S;Zhang Y;Childers W;Abou-Gharbia M;Karanicolas J;Baylin SB;Zahnow CA;Jelinek J;Graña X;Issa JJ
细胞周期蛋白依赖性激酶9(CDK9)通过RNAPII暂停释放促进转录延长。我们现在报道，CDK9在维持异色基因座的基因沉默方面也是必不可少的。通过具有遗传学确认的活细胞药物筛选，我们发现CDK9抑制在癌症中重新激活表观遗传沉默的基因，导致肿瘤抑制基因的恢复表达、细胞分化和内源性逆转录病毒基因的激活。抑制CDK9使SWI/SNF蛋白BRG1去磷酸化，从而促进基因重新激活。通过基因表达优化，我们开发出了一种高选择性的CDK9抑制剂(MC180295，IC50=5 nm)，它在体外具有广泛的抗癌活性，并在体内肿瘤模型中有效。此外，CDK9抑制在体内对免疫检查点抑制剂α-PD-1敏感，使其成为癌症表观遗传治疗的极佳靶点。抑制通常与异染色质形成相关的激酶导致肿瘤抑制基因的重新激活，并在癌症模型中增加对免疫治疗的敏感性
Cyclin-Dependent Kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50=5nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer. Inhibition of a kinase typically associated with heterochromatin formation leads to reactivation of tumor suppressor genes and increase sensitivity to immunotherapy in cancer models
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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影响因子：
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作者：
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通讯作者：
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