PXD038617

PXD038617 is an original dataset announced via ProteomeXchange.

Title	SUMO pulldown, U2OS, proteomics, 4 hour 20 hour 5-Aza-2' deoxycytidine treatment
Description	Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2’-deoxycytidine (5-Aza-2’) enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2’ to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2’. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2’ (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. In contrast, single dosing of TAK981 was ineffective and single dosing of 5-Aza-2’ only led to a modest outgrowth reduction. TAK981 and 5-Aza-2’ synergize to reduce B cell Lymphoma outgrowth in vitro and in vivo. SUMOylation is a key-player in the repair of DNA damage, hence upon TAK981 treatment the repair of DNA damage induced by 5-Aza-2’ treatment is impaired. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:59:55.215.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alfred Vertegaal
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-07 06:01:39	ID requested
1	2023-03-17 02:33:46	announced
⏵ 2	2023-11-14 08:59:55	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: 5-Aza-2' deoxycytidine, B cell lymphoma,SUMOylation

Alfred Vertegaal
contact affiliation	Leiden University Medical Centre (LUMC)
contact email	A.C.O.vertegaal@lumc.nl
lab head
Alfred Vertegaal
contact affiliation	Leiden University Medical Center
contact email	vertegaal@lumc.nl
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/2023/03/PXD038617

PRIDE project URI

• PRIDE
  1. PXD038617
     1. Label: PRIDE project
     2. Name: SUMO pulldown, U2OS, proteomics, 4 hour 20 hour 5-Aza-2' deoxycytidine treatment