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Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

2018; Cell Press; Volume: 175; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2018.09.051

1097-4172

Hanghang Zhang, Somnath Pandey, Meghan Travers, Hongxing Sun, George Morton, Jozef Madžo, Woonbok Chung, Jittasak Khowsathit, Óscar Cano Pérez, Carlos A. Barrero, Carmen Merali, Yasuyuki Okamoto, Takahiro Sato, Joshua Pan, Judit Garriga, Natarajan V. Bhanu, Johayra Simithy, Bela Patel, Jian Huang, Noël J.‐M. Raynal, Benjamin A. García, Marlene A. Jacobson, Cigall Kadoch, Salim Merali, Yi Zhang, Wayne E. Childers, Magid Abou‐Gharbia, John Karanicolas, Stephen B. Baylin, Cynthia A. Zahnow, Jaroslav Jelı́nek, Xavier Graña, Jean‐Pierre J. Issa,

Genetics and Neurodevelopmental Disorders

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.