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Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.
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, Noël 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; Graña, Xavier; Issa, Jean-Pierre J.
Afiliação
  • Zhang H; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Pandey S; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Travers M; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
  • Sun H; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Morton G; Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Madzo J; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Chung W; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Khowsathit J; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
  • Perez-Leal O; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Barrero CA; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Merali C; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Okamoto Y; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Sato T; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Pan J; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Garriga J; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Bhanu NV; Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Simithy J; Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Patel B; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Huang J; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Raynal NJ; Département de pharmacologie et physiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
  • Garcia BA; Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Jacobson MA; Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Kadoch C; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Merali S; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Zhang Y; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Childers W; Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Abou-Gharbia M; Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • Karanicolas J; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • Baylin SB; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
  • Zahnow CA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
  • Jelinek J; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Graña X; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • Issa JJ; Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address: jpissa@temple.edu.
Cell ; 175(5): 1244-1258.e26, 2018 11 15.
Article em En | MEDLINE | ID: mdl-30454645
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinase 9 Dependente de Ciclina Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinase 9 Dependente de Ciclina Idioma: En Ano de publicação: 2018 Tipo de documento: Article