A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR PMID: 41882000

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2026 Mar 26;17(1):4421. doi: 10.1038/s41467-026-71207-3.

Yang Yi ^# ¹ ² , Yanqiang Li ^# ³ ⁴ ⁵ , Rui Wang ¹ , Xufen Yu ⁶ , Qi Liu ¹ , Chaehyun Yum ¹ , Yang Zhang ⁷ , Yuanyuan Qiao ⁸ ⁹ ¹⁰ , Aileen Szczepanski ¹¹ , Siqi Wu ¹ , Qiaqia Li ¹ , Ladan Fazli ¹² ¹³ , Jiangchuan Shen ¹⁴ , Xin Wang ³ ⁴ ⁵ , Xiaoling Li ¹⁵ , Ping Mu ¹⁵ , Edward M Schaeffer ¹ , Heather A Hundley ¹⁶ , Hengyao Niu ¹⁴ , Arul M Chinnaiyan ⁸ ⁹ ¹⁰ ¹⁷ ¹⁸ , Lu Wang ¹¹ , Jinjun Shi ⁷ , Jian Jin ⁶ , Xuesen Dong ¹² ¹³ , Wei Zhao ¹⁹ , Kaifu Chen ²⁰ ²¹ ²² , Qi Cao ²³ ²⁴

Affiliations

1. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
2. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
3. Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
4. Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
5. Prostate Cancer Program, Dana-Farber Harvard Cancer Center, 450, Brookline, MA, USA.
6. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7. Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
8. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
9. Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
10. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
11. Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
12. Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
13. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
14. Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA.
15. Department of Urology, School of Medicine, Yale University, New Haven, CT, USA.
16. Department of Biology, Indiana University, Bloomington, IN, USA.
17. Department of Urology, University of Michigan, Ann Arbor, MI, USA.
18. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
19. Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.
20. Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, USA. [email protected].
21. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. [email protected].
22. Prostate Cancer Program, Dana-Farber Harvard Cancer Center, 450, Brookline, MA, USA. [email protected].
23. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
24. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. [email protected].
# Contributed equally.

Abstract

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a widespread modification in metazoans. Cumulative evidence has revealed the altered A-to-I editing profiles in cancers, but the underlying mechanism remains unclear. Here, we discover the well-known histone lysine methyltransferase enhancer of zeste homologue 2 (EZH2) as an unexplored ADAR interactor and editing regulator in prostate Cancer (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 ADAR1p110 isoform to protect many oncogenic transcripts from degradation. Consistently, depletion of ADAR1 dramatically enhances the sensitivity of Cancer cells and tumors to EZH2 selective degraders. Collectively, our study sheds new light on a link between two layers of epigenetic regulations at histone modification and RNA editing levels, demonstrates a previously uncharacterized role of EZH2 in RNA editing and mRNA stability independently of its lysine methyltransferase activity, and reveals the significance of EZH2-ADAR1 cascade in governing RNA editing and mRNA stability, which may provide additional perspectives for the advancement of EZH2-targeting Cancer therapies.