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

Shengrui Feng1,2, Sajid A Marhon3, Dustin J Sokolowski4,5

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. shengrui.feng@uhn.ca.

Nature Communications
|October 30, 2024
PubMed

Insights

Inactivating SMARCB1 mutations in atypical teratoid rhabdoid tumors (ATRTs) create a dependency on EZH2. EZH2 inhibition triggers a viral mimicry response via intronic Alu elements and LINE-1 activation, sensitizing ATRTs to treatment.

Area of Science:

  • Oncology
  • Epigenetics
  • Virology

Background:

  • Inactivating mutations in the SMARCB1 gene are linked to atypical teratoid rhabdoid tumors (ATRTs).
  • These tumors exhibit an oncogenic dependency on EZH2, a key epigenetic regulator.
  • The precise mechanism driving ATRT sensitivity to EZH2 inhibition remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which EZH2 inhibition (EZH2i) affects SMARCB1-deficient ATRTs.
  • To investigate the role of viral mimicry in the response to EZH2i.
  • To identify potential therapeutic targets in ATRTs.

Main Methods:

  • Analysis of gene expression changes in ATRTs upon EZH2 inhibition.
  • Investigation of the role of intronic inverted-repeat Alu (IR-Alu) elements and LINE-1 elements.
  • Assessment of the cGAS/STING signaling pathway and dsRNA sensing mechanisms.
  • Experimental manipulation of dsRNA and DNA sensing pathways.

Main Results:

  • EZH2 inhibition in ATRTs induces a viral mimicry response, not through endogenous retroelements, but via increased expression of genes containing intronic IR-Alu elements.
  • Interferon-stimulated genes (ISGs) enriched with dsRNA-forming intronic IR-Alu elements may create a feedforward loop for viral mimicry.
  • EZH2i upregulates full-length LINE-1 expression, causing genomic instability and activating cGAS/STING signaling dependent on reverse transcriptase activity.
  • Simultaneous depletion of dsRNA and cytoplasmic DNA sensing pathways abrogates the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

Conclusions:

  • The sensitivity of ATRTs to EZH2 inhibition is mediated by a viral mimicry response involving intronic IR-Alu elements and LINE-1 activation.
  • This response activates innate immune signaling pathways, presenting a potential therapeutic vulnerability in SMARCB1-deficient tumors.
  • Targeting dsRNA and DNA sensing pathways alongside EZH2 inhibition could be a promising therapeutic strategy for ATRTs.

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