PXD008040

PXD008040 is an original dataset announced via ProteomeXchange.

Title	SMARCA4 Phosphorilation inhibition
Description	Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation and high-level gene expression. 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 maintains gene silencing directly through phosphorylation of the SWI/SNF protein SMARCA4 and indirectly through HP1α activation. Based on gene activation, we developed the highly selective and 2 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 synergizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:00:44.649.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Carlos Barrero
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	carbamoylated residue; monohydroxylated residue; acetylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2017-10-25 03:15:34	ID requested
1	2023-06-13 14:36:41	announced
⏵ 2	2023-11-14 09:00:49	announced	2023-11-14: Updated project metadata.

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: Biological

submitter keyword: Phosphoproteomics, Colon Cancer Cells, LC-MS/MS

Salim Merali
contact affiliation	Professor of Pharmaceutical Sciences & Moulder Center for Drug Discovery Professor Lewis Katz School of Medicine Member Fox Chase Cancer Institute Director of Proteomics/Metabolomics Temple University School of Pharmacy
contact email	smerali@temple.edu
lab head
Carlos Barrero
contact affiliation	Assistant Professor Pharmacy School Temple University
contact email	cbarrero@temple.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/2023/06/PXD008040

PRIDE project URI

• PRIDE
  1. PXD008040
     1. Label: PRIDE project
     2. Name: SMARCA4 Phosphorilation inhibition