| Literature DB >> 30454645 |
Hanghang Zhang1, Somnath Pandey1, Meghan Travers2, Hongxing Sun1, George Morton3, Jozef Madzo1, Woonbok Chung1, Jittasak Khowsathit4, Oscar Perez-Leal5, Carlos A Barrero5, Carmen Merali5, Yasuyuki Okamoto1, Takahiro Sato1, Joshua Pan6, Judit Garriga1, Natarajan V Bhanu7, Johayra Simithy7, Bela Patel1, Jian Huang1, Noël J-M Raynal8, Benjamin A Garcia7, Marlene A Jacobson3, Cigall Kadoch6, Salim Merali5, Yi Zhang1, Wayne Childers3, Magid Abou-Gharbia3, John Karanicolas9, Stephen B Baylin2, Cynthia A Zahnow2, Jaroslav Jelinek1, Xavier Graña1, Jean-Pierre J Issa10.
Abstract
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.Entities:
Keywords: BRG1; CDK9; DNA methylation; SMARCA4; SWI/SNF; drug development; epigenetic therapy; gene silencing; immunosensitization; kinase inhibitors
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Year: 2018 PMID： 30454645 PMCID： PMC6247954 DOI： 10.1016/j.cell.2018.09.051
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582