Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

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 and Daniel D. De Carvalho ()
Additional contact information
Parinaz Mehdipour: University Health Network
Sajid A. Marhon: University Health Network
Ilias Ettayebi: University Health Network
Ankur Chakravarthy: University Health Network
Amir Hosseini: University Health Network
Yadong Wang: University Health Network
Fabíola Attié Castro: University Health Network
Helen Loo Yau: University Health Network
Charles Ishak: University Health Network
Sagi Abelson: Ontario Institute for Cancer Research
Catherine A. O’Brien: University Health Network
Daniel D. De Carvalho: University Health Network

Nature, 2020, vol. 588, issue 7836, 169-173

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2844-1

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