Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Epigenetic therapies activate endogenous retroelements, producing double-stranded RNA (dsRNA) that triggers antiviral responses in cancer cells.
• Clinical efficacy of epigenetic therapies is limited, necessitating strategies to enhance their anti-cancer effects.
• Identifying specific retroelements activated by epigenetic drugs is crucial for synergistic therapeutic approaches.

Purpose of the Study:

• To identify the specific retroelements responsible for drug-induced immunogenic dsRNA production.
• To elucidate the mechanism by which epigenetic therapies induce viral mimicry.
• To explore the potential of targeting ADAR1 to potentiate epigenetic cancer therapy.

Main Methods:

• Analysis of retroelement activation by epigenetic therapies in cancer cells.
• Investigation of dsRNA production and MDA5 receptor activation.
• Assessment of ADAR1's role in regulating the viral mimicry response.
• Evaluation of combined epigenetic therapy and ADAR1 inhibition in preclinical cancer models.

Main Results:

• Drug-induced immunogenic dsRNA primarily originates from inverted-repeat Alu elements, a type of SINE retroelement.
• ADAR1 enzyme destabilizes inverted-repeat Alu dsRNA, acting as a negative feedback regulator of the viral mimicry response.
• Depletion of ADAR1 enhances the efficacy of epigenetic therapy, suppressing tumor growth and cancer initiation in patient-derived cells.

Conclusions:

• Epigenetic therapies induce viral mimicry by activating specific inverted-repeat Alu elements, creating a dependency on ADAR1.
• Combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy to overcome limitations and improve cancer treatment outcomes.