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Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways
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Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways
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Journal Article
Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways
2024
Overview
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.
Here the authors suggest that in Atypical Teratoid Rhabdoid Tumors, EZH2 inhibition triggers a viral mimicry response via the activation of genes with intronic IR-Alu elements. This response also involves enhanced LINE-1 expression, leading to activation of cGAS/STING signalling.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/51
/ 38/90
/ 45/41
/ 45/88
/ 45/91
/ 82/1
/ 96/2
/ Animals
/ DNA
/ Enhancer of Zeste Homolog 2 Protein - genetics
/ Enhancer of Zeste Homolog 2 Protein - metabolism
/ Gene Expression Regulation, Neoplastic
/ Genes
/ Humanities and Social Sciences
/ Humans
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Mimicry
/ Nucleotidyltransferases - genetics
/ Nucleotidyltransferases - metabolism
/ RNA, Double-Stranded - metabolism
/ Science
/ SMARCB1 Protein - metabolism
/ Tumors
