PXD067850-1

PXD067850 is an original dataset announced via ProteomeXchange.

Title	PRC2 loss impairs small cell lung cancer tumorigenesis and enhances sensitivity to G9a/GLP inhibition
Description	Effective targeted therapies remain a major challenge for patients with small cell lung cancer (SCLC). Targeting the epigenome of SCLC to address immune evasion and chemoresistance offers a promising strategy to improve treatment outcomes. In this study, we investigate the role of Polycomb repressive complex 2 (PRC2), a major transcriptional repressor, by distinguishing its structural versus enzymatic functions. Conditional deletion of Eed, a core structural component of PRC2, prevented tumor formation in an autochthonous SCLC model. In contrast, enzymatic inhibition of EZH2 did not alter tumor growth. However, EZH2 inhibition significantly altered its interactome, revealing novel targets for drug development. Given that EZH2 inhibitors are clinically approved for other cancers, we conducted a focused drug screen to improve the therapeutic potential of EZH2. We found that prolonged EZH2 inhibition sensitized neuroendocrine cancer cells to G9a/GLP inhibition. Transcriptomic analysis revealed that this combination induced an oxidative stress response by modulating the expression of cellular oxidases, an effect that could be reversed by antioxidant treatment. These results highlight the critical role of PRC2 structural activity in SCLC and identify promising drug combinations to enhance the efficacy of EZH2 inhibitors.
HostingRepository	PRIDE
AnnounceDate	2025-12-16
AnnouncementXML	Submission_2025-12-16_06:25:40.680.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Miguel Hernandez Quiles
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-28 10:27:06	ID requested
⏵ 1	2025-12-16 06:25:41	announced

Dataset with its publication pending

submitter keyword: Small cell lung cancer, combination therapy, preclinical models, EED, EZH2, targeted therapy

Michiel Vermeulen
contact affiliation	Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands
contact email	mi.vermeulen@nki.nl
lab head
Miguel Hernandez Quiles
contact affiliation	Netherlands Cancer Institute
contact email	m.hernandez@nki.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067850
     1. Label: PRIDE project
     2. Name: PRC2 loss impairs small cell lung cancer tumorigenesis and enhances sensitivity to G9a/GLP inhibition