Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Author(s):Show less -

Mehdipour, Parinaz ^[1] ; Marhon, Sajid A. ^[1] ; Ettayebi, Ilias ^{[2, 1]} ; Chakravarthy, Ankur ^[1] ; Hosseini, Amir ^[1] ; Wang, Yadong ^[1] ; de Castro, Fabiola Attie ^{[1, 3]} ; Loo Yau, Helen ^{[2, 1]} ; Ishak, Charles ^[1] ; Abelson, Sagi ^{[4, 5]} ; O'Brien, Catherine A. ^{[2, 6, 7, 1, 8]} ; De Carvalho, Daniel D. ^{[2, 1]}

Affiliation

^[1] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON - Canada

^[2] Univ Toronto, Dept Med Biophys, Toronto, ON - Canada

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, Ribeirao Preto - Brazil

^[4] Univ Toronto, Dept Mol Genet, Toronto, ON - Canada

^[5] Ontario Inst Canc Res, Toronto, ON - Canada

^[6] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON - Canada

^[7] Univ Toronto, Dept Physiol, Toronto, ON - Canada

^[8] Toronto Gen Hosp, Dept Surg, Toronto, ON - Canada

• Document type: Journal article
• Source: Nature; v. 588, n. 7836, p. 169+, DEC 3 2020.
• Web of Science Citations: 10

Abstract

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. 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. (AU)

• FAPESP's process: 15/21237-4 - DNA METHYLATION PROFILE OF PRE-LEUKEMIC AND LEUKEMIC HEMATOPOIETIC STEM CELLS FROM ACUTE MYELOID LEUKEMIA DETECTED BY A SINGLE CELL DNA METHYLATION ASSAY
• Grantee: Fabíola Attié de Castro
• Support Opportunities: Scholarships abroad - Research