期刊
CELL
卷 175, 期 5, 页码 1244-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.09.051
关键词
-
资金
- NIH [CA158112, CA100632, GM117437, CA216134-01, GM110174, GM123336, DK105267]
- Van Andel Research Institute through the Van Andel Research Institute-Stand Up To Cancer Epigenetics Dream Team
- National Science Foundation [ACI1548562]
- F.M. Kirby Foundation
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 alpha-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据