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

Author

Listed:
  • Shengrui Feng

    (University Health Network
    The First Affiliated Hospital of University of South China)

  • Sajid A. Marhon

    (University Health Network)

  • Dustin J. Sokolowski

    (University of Toronto
    SickKids Research Institute)

  • Alister D’Costa

    (University of Toronto
    Ontario Institute for Cancer Research)

  • Fraser Soares

    (University Health Network)

  • Parinaz Mehdipour

    (University Health Network
    University of Oxford)

  • Charles Ishak

    (University Health Network)

  • Helen Loo Yau

    (University Health Network
    University of Toronto)

  • Ilias Ettayebi

    (University Health Network
    University of Toronto)

  • Parasvi S. Patel

    (University Health Network
    University of Toronto)

  • Raymond Chen

    (University Health Network
    University of Toronto)

  • Jiming Liu

    (Sichuan University)

  • Philip C. Zuzarte

    (Ontario Institute for Cancer Research)

  • King Ching Ho

    (Hospital for Sick Children
    Hospital for Sick Children)

  • Ben Ho

    (University of Toronto)

  • Shiyao Ning

    (University Health Network)

  • Annie Huang

    (The First Affiliated Hospital of University of South China
    Hospital for Sick Children
    Hospital for Sick Children
    University of Toronto)

  • Cheryl H. Arrowsmith

    (University Health Network
    University of Toronto
    University of Toronto)

  • Michael D. Wilson

    (University of Toronto
    SickKids Research Institute)

  • Jared T. Simpson

    (University of Toronto
    Ontario Institute for Cancer Research)

  • Daniel D. Carvalho

    (University Health Network
    University of Toronto)

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.

Suggested Citation

  • 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 & Raymond Chen & Jiming, 2024. "Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53515-8
    DOI: 10.1038/s41467-024-53515-8
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