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, Raymond Chen, Jiming Liu, Philip C. Zuzarte, King Ching Ho, Ben Ho, Shiyao Ning, Annie Huang, Cheryl H. Arrowsmith, Michael D. Wilson, Jared T. Simpson and Daniel D. Carvalho ()
Additional contact information
Shengrui Feng: University Health Network
Sajid A. Marhon: University Health Network
Dustin J. Sokolowski: University of Toronto
Alister D’Costa: University of Toronto
Fraser Soares: University Health Network
Parinaz Mehdipour: University Health Network
Charles Ishak: University Health Network
Helen Loo Yau: University Health Network
Ilias Ettayebi: University Health Network
Parasvi S. Patel: University Health Network
Raymond Chen: University Health Network
Jiming Liu: Sichuan University
Philip C. Zuzarte: Ontario Institute for Cancer Research
King Ching Ho: 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
Cheryl H. Arrowsmith: University Health Network
Michael D. Wilson: University of Toronto
Jared T. Simpson: University of Toronto
Daniel D. Carvalho: University Health Network

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53515-8

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