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PXD007925

PXD007925 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer
DescriptionCyclin-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 dephosphorylates 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 =5.1nM) 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.
HostingRepositoryPRIDE
AnnounceDate2020-05-26
AnnouncementXMLSubmission_2020-05-26_11:12:29.xml
DigitalObjectIdentifierhttp://dx.doi.org/10.6019/PXD007925
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterZuo-Fei Yuan
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListphosphorylated residue; formylated residue; acetylated residue; propanoylated residue; butanoylated residue
InstrumentLTQ Orbitrap Velos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02017-10-09 03:56:13ID requested
12020-05-26 11:12:30announced
Publication List
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, Gra, ñ, a X, Issa JJ, Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell, 175(5):1244-1258.e26(2018) [pubmed]
Keyword List
curator keyword: Biomedical
submitter keyword: CDK9, gene silencing, epigenetic therapy, immunosensitization
Contact List
Benjamin A. Garcia
contact affiliationProfessor of Biochemistry and Biophysics, University of Pennsylvania School of Medicine
contact emailbgarci@pennmedicine.upenn.edu
lab head
Zuo-Fei Yuan
contact affiliationUPenn
contact emailzuoyuan@mail.med.upenn.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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