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    Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

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    TETDEDXZhang-temple-0225E-13147.pdf
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    Genre
    Thesis/Dissertation
    Date
    2017
    Author
    Zhang, Hanghang
    Advisor
    Issa, Jean-Pierre
    Committee member
    Sapienza, Carmen
    Graña-Amat, Xavier
    Jacobson, Marlene A.
    Department
    Molecular Biology and Genetics
    Subject
    Oncology
    Pharmacology
    Genetics
    Cdk9
    Dna Methylation
    Epigenetic Therapy
    Gene Silencing
    Immunosensitization
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/4092
    
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    DOI
    http://dx.doi.org/10.34944/dspace/4074
    Abstract
    Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation by promoting RNAPII pause release. We now report that, paradoxically, CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell screen, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression and cell differentiation, along with activation of endogenous retrovirus (ERV) genes. CDK9 inhibition results in dephorphorylation of the SWI/SNF protein SMARCA4 and represses HP1α expression, both of which contribute to gene reactivation. Based on gene activation, we developed the highly selective and potent CDK9 inhibitor MC180295 (IC50 =5nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
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