2. Academic Validation
  3. Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

  • Nature. 2020 Dec;588(7836):169-173. doi: 10.1038/s41586-020-2844-1.
Parinaz Mehdipour  # 1,  Sajid A Marhon  # 2,  Ilias Ettayebi  # 2 3,  Ankur Chakravarthy 2,  Amir Hosseini 2,  Yadong Wang 2,  Fabíola Attié de Castro 2 4,  Helen Loo Yau 2 3,  Charles Ishak 2,  Sagi Abelson 5 6,  Catherine A O'Brien 2 3 7 8 9,  Daniel D De Carvalho 10 11
Affiliations

Affiliations

  • 1 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. parinaz.mehdipour@uhnresearch.ca.
  • 2 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 4 Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
  • 5 Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 6 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 7 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 8 Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
  • 9 Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
  • 10 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca.
  • 11 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca.
  • # Contributed equally.
PMID: 33087935 DOI: 10.1038/s41586-020-2844-1
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.

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