PXD050643

PXD050643 is an original dataset announced via ProteomeXchange.

Title	Targeting cholesterol homeostasis eliminates drug-tolerant persister cells in glioblastoma
Description	The transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes drives treatment failures. Using glioblastoma models, we identified MRK-740, an inhibitor of H3K4 methyltransferase PRDM7/9, as a potent enhancer of chemotherapy-induced cell death, resulting in elimination of glioblastoma persister cells. Mechanistic investigations as well as analysis of glioblastoma specimens revealed that H3K4me3 is a transcription-activating mark at the promoters of key genes involved in cholesterol biosynthesis. The inhibition of H3K4 methylation in cells treated with microtubule-targeting agents led to the disruption of cholesterol homeostasis and LXR-dependent cholesterol efflux, ultimately depleting intracellular cholesterol and causing the death of persisters. Furthermore, we have developed a brain permeable microtubule-targeting agent to validate these mechanistic findings in vivo. We show that a combination of our novel chemotherapeutic agent and a brain permeable LXR agonist significantly extends survival in a glioblastoma mouse model. These results uncover the importance of balanced cholesterol homeostasis in chemotherapy tolerance.
HostingRepository	PRIDE
AnnounceDate	2025-12-22
AnnouncementXML	Submission_2025-12-21_19:23:09.406.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jason Low
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-15 01:47:29	ID requested
⏵ 1	2025-12-21 19:23:10	announced

10.1038/s41467-025-65888-5;

Joun GL, Kempe EG, Chen B, Sterling JR, Abbassi RH, Friess D, Singleton M, Choudhury C, Marian OC, du Preez WD, Recasens A, Clark T, Du TY, Low JKK, Kim H, Yang P, Khor J, Hoque M, Indurthi DC, Kuchibhotla M, Palanisamy R, Jorgensen WT, Montgomery AP, Baker JR, Higginbottom SL, Tomaskovic-Crook E, Crook JM, Loo L, Day BW, Neely GG, Guccione E, Johns TG, Kassiou M, Feng Y, Harris L, Don AS, Munoz L, Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma. Nat Commun, 16(1):10905(2025) [pubmed]

submitter keyword: Gliobastomas, histones, microtubule-targeting agents

Lenka Munoz
contact affiliation	School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia
contact email	lenka.munoz@sydney.edu.au
lab head
Jason Low
contact affiliation	The University of Sydney
contact email	jason.low@sydney.edu.au
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/2025/12/PXD050643

PRIDE project URI

• PRIDE
  1. PXD050643
     1. Label: PRIDE project
     2. Name: Targeting cholesterol homeostasis eliminates drug-tolerant persister cells in glioblastoma