A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR1

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a widespread modification in mammals. Cumulative evidence has suggested the altered A-to-I editing profile in prostate cancer (PCa), but the underlying mechanism remains unclear. Here, we discover enhancer of zeste homologue 2 (EZH2) as a novel ADAR interactor and editing regulator in PCa. Through competing with Interleukin Enhancer Binding Factor 2 (ILF2) for ADAR1 binding, EZH2 reshapes the substrate selectivity of ADAR1 and thus exhibits a bidirectional role in editing regulation. Moreover, EZH2 depletion induces the translational repression of Transportin-1 (TRN1), which further results in the accumulation of cytoplasmic ADAR1 to protect many oncogenic transcripts from degradation. Consistently, depletion of ADAR1 dramatically enhances the sensitivity of PCa cells and tumors to EZH2 selective degraders. Collectively, our study highlights the significance of EZH2-ADAR1 cascade in governing RNA editing and mRNA stability, which may provide novel perspectives for the advancement of EZH2-targeting cancer therapies.