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PXD017898

PXD017898 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleARID1A regulates transcription and the epigenetic landscape via POLE and DMAP1 while ARID1A deficiency or pharmacological inhibition sensitizes germ cell tumor cells to ATR inhibition
DescriptionGerm cell tumors (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved at early stages, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin, subsequently leading to induction of stress, apoptosis and cell cycle regulators. Additionally, ARID1A is mutated in many different tumor types, like bladder, breast or ovarial cancer. There, the loss-of-function mutations re-sensitize these tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate that ARID1A regulates transcription, DNA repair and the epigenetic landscape on DNA and histone level via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A deficiency or pharmacological inhibition considerably sensitized (cisplatin-resistant) GCT cells towards ATR inhibition. Thus, ARID1A might be new combination partner for ATR inhibitors in the treatment of GCTs.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:02:06.135.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterNina Overbeck
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-03-05 03:28:29ID requested
12020-04-13 22:42:50announced
22024-10-22 05:02:13announced2024-10-22: Updated project metadata.
Publication List
10.3390/cancers12040905;
Kurz L, Miklyaeva A, Skowron MA, Overbeck N, Poschmann G, Becker T, Eul K, Kurz T, Sch, ö, nberger S, Calaminus G, St, ü, hler K, Dykhuizen E, Albers P, Nettersheim D, Deficiency or Pharmacological Inhibition Sensitizes Germ Cell Tumor Cells to ATR Inhibition. Cancers (Basel), 12(4):(2020) [pubmed]
Keyword List
submitter keyword: molecular therapy, SWI/SNF-complex, mass spectrometry, HDAC inhibitors, CRISPR/Cas9, ATR inhibitors,ARID1A, germ cell tumors
Contact List
Kai Stühler
contact affiliationInstitute for Molecular Medicine I Medical Faculty Heinrich-Heine-University Duesseldorf Universitaetsstrasse 1 40225 Duesseldorf Germany
contact emailkai.stuehler@hhu.de
lab head
Nina Overbeck
contact affiliationBMFZ/MPL
contact emailnina.overbeck@hhu.de
dataset submitter
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Dataset FTP location
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PRIDE project URI
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