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Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Author

Listed:
  • Parinaz Mehdipour

    (University Health Network)

  • Sajid A. Marhon

    (University Health Network)

  • Ilias Ettayebi

    (University Health Network
    University of Toronto)

  • Ankur Chakravarthy

    (University Health Network)

  • Amir Hosseini

    (University Health Network)

  • Yadong Wang

    (University Health Network)

  • Fabíola Attié Castro

    (University Health Network
    University of São Paulo)

  • Helen Loo Yau

    (University Health Network
    University of Toronto)

  • Charles Ishak

    (University Health Network)

  • Sagi Abelson

    (Ontario Institute for Cancer Research
    University of Toronto)

  • Catherine A. O’Brien

    (University Health Network
    University of Toronto
    University of Toronto
    University of Toronto)

  • Daniel D. De Carvalho

    (University Health Network
    University of Toronto)

Abstract

Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor1–6. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses7,8. However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of ‘orphan’ CpG islands9. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA10, which prevents activation of the MDA5 receptor11. We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment.

Suggested Citation

  • Parinaz Mehdipour & Sajid A. Marhon & Ilias Ettayebi & Ankur Chakravarthy & Amir Hosseini & Yadong Wang & Fabíola Attié Castro & Helen Loo Yau & Charles Ishak & Sagi Abelson & Catherine A. O’Brien & D, 2020. "Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency," Nature, Nature, vol. 588(7836), pages 169-173, December.
  • Handle: RePEc:nat:nature:v:588:y:2020:i:7836:d:10.1038_s41586-020-2844-1
    DOI: 10.1038/s41586-020-2844-1
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    Cited by:

    1. Qin Yu & Alba Herrero del Valle & Rahul Singh & Yorgo Modis, 2021. "MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Jianheng Liu & Tao Huang & Jing Yao & Tianxuan Zhao & Yusen Zhang & Rui Zhang, 2023. "Epitranscriptomic subtyping, visualization, and denoising by global motif visualization," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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