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; Daniel D De Carvalho

doi:10.1038/s41467-024-53515-8

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

Nat Commun. 2024 Oct 29;15(1):9321. doi: 10.1038/s41467-024-53515-8.

Authors

Shengrui Feng^#^{1

2}, Sajid A Marhon^#³, Dustin J Sokolowski^#^{4

5}, Alister D'Costa^{6

7}, Fraser Soares³, Parinaz Mehdipour^{3

8}, Charles Ishak³, Helen Loo Yau^{3

9}, Ilias Ettayebi^{3

9}, Parasvi S Patel^{3

9}, Raymond Chen^{3

9}, Jiming Liu¹⁰, Philip C Zuzarte⁷, King Ching Ho^{11

12}, Ben Ho¹³, Shiyao Ning³, Annie Huang^{14

11

12

13}, Cheryl H Arrowsmith^{3

9

15}, Michael D Wilson^{4

5}, Jared T Simpson^{6

7}, Daniel D De Carvalho^{16

17}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
² The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. [email protected].
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁵ Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
⁶ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
⁷ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁸ Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁰ 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.
¹¹ Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
¹² Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
¹³ Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁴ The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
¹⁵ Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
¹⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
¹⁷ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [email protected].

^# Contributed equally.

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.

MeSH terms

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

Substances

Enhancer of Zeste Homolog 2 Protein
EZH2 protein, human
SMARCB1 Protein
SMARCB1 protein, human
RNA, Double-Stranded
STING1 protein, human
DNA
Membrane Proteins
Nucleotidyltransferases