Journal Article

Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

de Castro, Fabíola Attié, De Carvalho, Daniel D., Ettayebi, Ilias, Hosseini, Amir, Loo Yau, Helen, Ishak, Charles, Abelson, Sagi, Chakravarthy, Ankur, O’Brien, Catherine A., Mehdipour, Parinaz, Marhon, Sajid A., Wang, Yadong

2020

Overview

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 receptor 1 – 6 . This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses 7 , 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 islands 9 . In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA 10 , which prevents activation of the MDA5 receptor 11 . 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. Inverted-repeat Alu elements are the main source of drug-induced immunogenic double-stranded RNAs, which are destabilized by the RNA deaminase ADAR1, thereby limiting activation of the immune response.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 38/91 / 631/1647/2210 / 631/208/176 / 631/208/177 / 631/67/1059 / Adaptive immunity / Adaptive Immunity - drug effects / Adenosine Deaminase - deficiency / Adenosine Deaminase - metabolism / Alu Elements - drug effects / Alu Elements - genetics / Alu Elements - immunology / Animals / Cancer / Cell Line, Tumor / CpG islands / CpG Islands - drug effects / CpG Islands - genetics / Decitabine - pharmacology / Decitabine - therapeutic use / Dependence / Depletion / DNA, Intergenic - drug effects / DNA, Intergenic - genetics / DNA, Intergenic - immunology / DNA-Cytosine Methylases - antagonists & inhibitors / Double-stranded RNA / Enzymes / Epigenesis, Genetic - drug effects / Epigenetics / Feedback loops / Feedback, Physiological / Genomes / Humanities and Social Sciences / Humans / Immunity, Innate - drug effects / Immunogenicity / Interferon-Induced Helicase, IFIH1 - metabolism / Introns - drug effects / Introns - genetics / Introns - immunology / Inverted Repeat Sequences - drug effects / Inverted Repeat Sequences - genetics / Inverted Repeat Sequences - immunology / Male / Mice / Mimicry / Molecular Mimicry - drug effects / Molecular Mimicry - immunology / multidisciplinary / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - immunology / Neoplasms - pathology / Pattern recognition / Pattern recognition receptors / Repressors / RNA, Double-Stranded - drug effects / RNA, Double-Stranded - genetics / RNA, Double-Stranded - immunology / RNA-Binding Proteins - antagonists & inhibitors / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Synergism / Therapy / Transcription / Transcription, Genetic - drug effects / Tumors / Viruses - drug effects / Viruses - immunology