Evidence map›Paper›PMID 39472584›Full record

ArticleNature communications2024

Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways.

Shengrui Feng, Sajid A Marhon, Dustin J Sokolowski, Alister D'Costa, Fraser Soares, Parinaz Mehdipour, Charles Ishak, Helen Loo Yau, Ilias Ettayebi, Parasvi S Patel and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Shengrui Feng *Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. shengrui.feng@uhn.ca.ORCID 0000-0002-5321-5529
Sajid A Marhon *Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0002-1046-9852
Dustin J Sokolowski *Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Alister D'CostaDepartment of Computer Science, University of Toronto, Toronto, ON, Canada.
Fraser SoaresPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0002-3977-7939
Parinaz MehdipourPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0002-4476-9925
Charles IshakPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Helen Loo YauPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0003-4867-8593
Ilias EttayebiPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Parasvi S PatelPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Raymond ChenPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Jiming LiuThe Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China.
Philip C ZuzarteOntario Institute for Cancer Research, Toronto, ON, Canada.
King Ching HoDivision of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
Ben HoLaboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Shiyao NingPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0003-4635-8270
Annie HuangThe First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
Cheryl H ArrowsmithPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0002-4971-3250
Michael D WilsonDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada.ORCID 0000-0002-4015-3066
Jared T SimpsonDepartment of Computer Science, University of Toronto, Toronto, ON, Canada.
Daniel D De CarvalhoPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. daniel.decarvalho@uhnresearch.ca.ORCID 0000-0002-8572-5259

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypical teratoid rhabdoid tumors (ATRTs), but the underlying mechanism has not been fully elucidated. We found that the sensitivity of ATRTs to EZH2 inhibition (EZH2i) is associated with the viral mimicry response. Unlike other epigenetic therapies targeting transcriptional repressors, EZH2i-induced viral mimicry is not triggered by cryptic transcription of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a feedforward loop whereby these activated ISGs may reinforce dsRNA formation and viral mimicry. EZH2i also upregulates the expression of full-length LINE-1s, leading to genomic instability and cGAS/STING signaling in a process dependent on reverse transcriptase activity. Co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

Indexed as

Enhancer of Zeste Homolog 2 ProteinRhabdoid TumorSMARCB1 ProteinAlu ElementsAnimalsCell Line, TumorDNAGene Expression Regulation, NeoplasticGenomic InstabilityHumansMembrane ProteinsMiceMolecular MimicryNucleotidyltransferasesRNA, Double-StrandedSignal TransductionDNAEnhancer of Zeste Homolog 2 ProteinEZH2 protein, humanMembrane ProteinsNucleotidyltransferasesRNA, Double-StrandedSMARCB1 ProteinSMARCB1 protein, humanSTING1 protein, humanSTING Protein

Identifiers

PMID39472584
PMCPMC11522499

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.