Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency
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. This state of viral mimicry leads to loss of cancer ce...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2020
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| _version_ | 1797060095966707712 |
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| author | Mehdipour, P Marhon, SA Ettayebi, I Chakravarthy, A Hosseini, A Wang, Y de Castro, FA Loo Yau, H Ishak, C Abelson, S O’Brien, CA De Carvalho, DD |
| author_facet | Mehdipour, P Marhon, SA Ettayebi, I Chakravarthy, A Hosseini, A Wang, Y de Castro, FA Loo Yau, H Ishak, C Abelson, S O’Brien, CA De Carvalho, DD |
| author_sort | Mehdipour, P |
| collection | OXFORD |
| description | 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. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses. 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. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA, which prevents activation of the MDA5 receptor. 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. |
| first_indexed | 2024-03-06T20:12:47Z |
| format | Journal article |
| id | oxford-uuid:2b25bafc-940c-423c-b70f-9e20854f3e79 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:12:47Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:2b25bafc-940c-423c-b70f-9e20854f3e792022-03-26T12:29:11ZEpigenetic therapy induces transcription of inverted SINEs and ADAR1 dependencyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2b25bafc-940c-423c-b70f-9e20854f3e79EnglishSymplectic ElementsSpringer Nature2020Mehdipour, PMarhon, SAEttayebi, IChakravarthy, AHosseini, AWang, Yde Castro, FALoo Yau, HIshak, CAbelson, SO’Brien, CADe Carvalho, DDCancer 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. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses. 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. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA, which prevents activation of the MDA5 receptor. 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. |
| spellingShingle | Mehdipour, P Marhon, SA Ettayebi, I Chakravarthy, A Hosseini, A Wang, Y de Castro, FA Loo Yau, H Ishak, C Abelson, S O’Brien, CA De Carvalho, DD Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency |
| title | Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency |
| title_full | Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency |
| title_fullStr | Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency |
| title_full_unstemmed | Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency |
| title_short | Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency |
| title_sort | epigenetic therapy induces transcription of inverted sines and adar1 dependency |
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