PXD007925

PXD007925 is an original dataset announced via ProteomeXchange.

Title	Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer
Description	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 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.
HostingRepository	PRIDE
AnnounceDate	2020-05-26
AnnouncementXML	Submission_2020-05-26_11:12:29.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD007925
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Zuo-Fei Yuan
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; formylated residue; acetylated residue; propanoylated residue; butanoylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2017-10-09 03:56:13	ID requested
⏵ 1	2020-05-26 11:12:30	announced

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]

curator keyword: Biomedical

submitter keyword: CDK9, gene silencing, epigenetic therapy, immunosensitization

Benjamin A. Garcia
contact affiliation	Professor of Biochemistry and Biophysics, University of Pennsylvania School of Medicine
contact email	bgarci@pennmedicine.upenn.edu
lab head
Zuo-Fei Yuan
contact affiliation	UPenn
contact email	zuoyuan@mail.med.upenn.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/05/PXD007925

PRIDE project URI

• PRIDE
  1. PXD007925
     1. Label: PRIDE project
     2. Name: Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer