Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Cell. 2018 Nov 15;175(5):1244-1258.e26. doi: 10.1016/j.cell.2018.09.051. Epub 2018 Oct 25.
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 = 5 nM) 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.
细胞周期蛋白依赖性激酶 9（CDK9）通过促进 RNAPII 暂停释放来促进转录延伸。我们现在报告称，CDK9 对于维持异染色质区域的基因沉默也是必不可少的。通过使用遗传确认的活细胞药物筛选，我们发现 CDK9 抑制可使癌症中表观遗传沉默的基因重新激活，导致肿瘤抑制基因表达的恢复、细胞分化和内源性逆转录病毒基因的激活。CDK9 抑制使 SWI/SNF 蛋白 BRG1 去磷酸化，这有助于基因的重新激活。通过基因表达的优化，我们开发了一种高度选择性的 CDK9 抑制剂（MC180295，IC50=5 nM），该抑制剂在体外具有广泛的抗癌活性，在体内癌症模型中也有效。此外，CDK9 抑制使免疫检查点抑制剂 α-PD-1 在体内敏感，使其成为癌症表观遗传治疗的优秀靶标。
