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dc.contributor.advisorIssa, Jean-Pierre
dc.creatorZhang, Hanghang
dc.date.accessioned2020-11-05T19:50:47Z
dc.date.available2020-11-05T19:50:47Z
dc.date.issued2017
dc.identifier.urihttp://hdl.handle.net/20.500.12613/4092
dc.description.abstractCyclin-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.
dc.format.extent152 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectOncology
dc.subjectPharmacology
dc.subjectGenetics
dc.subjectCdk9
dc.subjectDna Methylation
dc.subjectEpigenetic Therapy
dc.subjectGene Silencing
dc.subjectImmunosensitization
dc.titleTargeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberSapienza, Carmen
dc.contributor.committeememberGraña, Xavier
dc.contributor.committeememberJacobson, Marlene A.
dc.description.departmentMolecular Biology and Genetics
dc.relation.doihttp://dx.doi.org/10.34944/dspace/4074
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-11-05T19:50:47Z


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