PLX028047

GSE145639: Epigenetic therapy induces transcription of Inverted SINEs and ADAR1 dependency

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

In this study we show that intronic and intergenic SINE elements, specifically inverted repeats (IR) Alus, are the major source of drug-induced immunogenic dsRNA. These IR-Alus are frequently located downstream of orphan CpG Islands (CGIs). In mammals, the enzyme Adenosine Deaminases Acting on RNA (ADAR1) targets and destabilizes IR-Alu dsRNA, which prevents activation of MDA5. 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. Thus, epigenetic therapies trigger viral mimicry by inducing a subset of IR-Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising new strategy for cancer treatment. SOURCE: Sajid,A,Marhon (sajid.marhon@gmail.com) - Princess Margaret Cancer Centre