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

Enhancer of Zeste Homolog 2 Protein / metabolism Humans Rhabdoid Tumor / genetics SMARCB1 Protein / metabolism Cell Line, Tumor Signal Transduction Alu Elements / genetics RNA, Double-Stranded / metabolism Gene Expression Regulation, Neoplastic Mice DNA / metabolism Animals Membrane Proteins / metabolism Molecular Mimicry Genomic Instability Nucleotidyltransferases / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
29 Oct 2024
Historique:
received: 01 03 2023
accepted: 12 10 2024
medline: 30 10 2024
pubmed: 30 10 2024
entrez: 30 10 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-53515-8 PMID: 39472584
pubmed: 39472584
doi: 10.1038/s41467-024-53515-8
pii: 10.1038/s41467-024-53515-8
doi:

Substances chimiques

Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43
EZH2 protein, human EC 2.1.1.43
SMARCB1 Protein 0
SMARCB1 protein, human 0
RNA, Double-Stranded 0
STING1 protein, human 0
DNA 9007-49-2
Membrane Proteins 0
Nucleotidyltransferases EC 2.7.7.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

9321

Informations de copyright

© 2024. The Author(s).

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Auteurs

Shengrui Feng (S)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. shengrui.feng@uhn.ca.
The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. shengrui.feng@uhn.ca.
ORCID: 0000-0002-5321-5529

Sajid A Marhon (SA)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
ORCID: 0000-0002-1046-9852

Dustin J Sokolowski (DJ)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.

Alister D'Costa (A)

Department of Computer Science, University of Toronto, Toronto, ON, Canada.
Ontario Institute for Cancer Research, Toronto, ON, Canada.

Fraser Soares (F)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
ORCID: 0000-0002-3977-7939

Parinaz Mehdipour (P)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
ORCID: 0000-0002-4476-9925

Charles Ishak (C)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Helen Loo Yau (H)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0003-4867-8593

Ilias Ettayebi (I)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Parasvi S Patel (PS)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Raymond Chen (R)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Jiming Liu (J)

The 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 Zuzarte (PC)

Ontario Institute for Cancer Research, Toronto, ON, Canada.

King Ching Ho (KC)

Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada.

Ben Ho (B)

Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Shiyao Ning (S)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
ORCID: 0000-0003-4635-8270

Annie Huang (A)

The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Cheryl H Arrowsmith (CH)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0002-4971-3250

Michael D Wilson (MD)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
ORCID: 0000-0002-4015-3066

Jared T Simpson (JT)

Department of Computer Science, University of Toronto, Toronto, ON, Canada.
Ontario Institute for Cancer Research, Toronto, ON, Canada.

Daniel D De Carvalho (DD)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. daniel.decarvalho@uhnresearch.ca.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. daniel.decarvalho@uhnresearch.ca.
ORCID: 0000-0002-8572-5259

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Protéines du groupe Polycomb › Complexe répresseur Polycomb-2 › Protéine-2 homologue de l'activateur de Zeste › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs complexes et mixtes › Tumeur rhabdoïde › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéine SMARCB1 › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées dispersées › Rétroéléments › Éléments SINE › Séquences Alu › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › ARN double brin › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › Inhibiting EZH2 targets atypical teratoid...
questionsmedicales.fr › Eucaryotes › Animaux › Inhibiting EZH2 targets atypical teratoid...
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