PXD069619-1

PXD069619 is an original dataset announced via ProteomeXchange.

Title	Antagonistic roles of histone 3 lysine methyltransferases dictate tumor immune surveillance
Description	Histone H3 lysine 36 (H3K36) methyltransferases are frequently mutated in cancer, but their functional roles remain unclear. Using functional genomics approaches within KRAS-driven lung cancer models, we show that NSD2, SETD2, and EZH2 work in concert to regulate expression of endogenous retroviral elements, which act as a molecular rheostat controlling immune surveillance. Specifically, loss of H3K36me2 and H3K36me3 activity through H3K36M oncohistone expression or H3K36me2 alone through NSD2 inactivation leads to derepression of endogenous retroviral element transcripts that activate a dsRNA-mediated antiviral-like immune response that potently eradicates KRAS-driven tumor growth. Surprisingly, derepression of ERV sequences and subsequent immune reactions are completely dependent on SETD2, a tumor suppressor in KRAS-driven lung cancer that directly mediates H3K36me3 deposition. Mechanistically, inactivation of both NSD2 and SETD2 attenuates immune reactions by activating EZH2-dependent H3K27me3 and transcript repression at ERV sequences. These findings define an enzymatic triad of NSD2, SETD2, and EZH2 whose coordinated activities link chromatin regulation and tumor immune surveillance, revealing new epigenetic vulnerabilities in cancer.
HostingRepository	PRIDE
AnnounceDate	2026-07-22
AnnouncementXML	Submission_2026-07-22_14:04:49.578.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simone Sidoli
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monomethylated residue; acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-18 14:17:26	ID requested
⏵ 1	2026-07-22 14:04:50	announced

Dataset with its publication pending

submitter keyword: NSD2, epigenetic vulnerability, immune surveillance, chromatin regulation, ERVs, KRAS lung cancer,H3K36 methylation, EZH2, SETD2, H3K36M

Simone Sidoli
contact affiliation	Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, United States
contact email	simone.sidoli@einsteinmed.edu
lab head
Simone Sidoli
contact affiliation	Albert Einstein College of Medicine
contact email	simone.sidoli@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069619
     1. Label: PRIDE project
     2. Name: Antagonistic roles of histone 3 lysine methyltransferases dictate tumor immune surveillance