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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 , Grana X , Issa JJ
Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer
Cell. 2018 Nov 15;175(5) :1244-1258.e26
PMID: 30454645 PMCID: PMC6247954
AbstractCyclin-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.
Notes1097-4172 Zhang, Hanghang Pandey, Somnath Travers, Meghan Sun, Hongxing Morton, George Madzo, Jozef Chung, Woonbok Khowsathit, Jittasak Perez-Leal, Oscar Barrero, Carlos A Merali, Carmen Okamoto, Yasuyuki Sato, Takahiro Pan, Joshua Garriga, Judit Bhanu, Natarajan V Simithy, Johayra Patel, Bela Huang, Jian Raynal, Noel J-M Garcia, Benjamin A Jacobson, Marlene A Kadoch, Cigall Merali, Salim Zhang, Yi Childers, Wayne Abou-Gharbia, Magid Karanicolas, John Baylin, Stephen B Zahnow, Cynthia A Jelinek, Jaroslav Grana, Xavier Issa, Jean-Pierre J R03 DK105267/DK/NIDDK NIH HHS/United States P50 CA100632/CA/NCI NIH HHS/United States R01 CA158112/CA/NCI NIH HHS/United States R01 HL127351/HL/NHLBI NIH HHS/United States P01 CA196539/CA/NCI NIH HHS/United States R01 CA172106/CA/NCI NIH HHS/United States R01 GM123336/GM/NIGMS NIH HHS/United States R03 CA216134/CA/NCI NIH HHS/United States R01 CA214005/CA/NCI NIH HHS/United States R01 AI118891/AI/NIAID NIH HHS/United States R01 GM110174/GM/NIGMS NIH HHS/United States R01 GM117437/GM/NIGMS NIH HHS/United States Journal Article United States Cell. 2018 Nov 15;175(5):1244-1258.e26. doi: 10.1016/j.cell.2018.09.051. Epub 2018 Oct 25.