Affiliations
1Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599.
2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600; Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong.
3Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; The N.1 Institute for Health (N.1), 28 Medical Dr, Singapore 117456.
4Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371.
5Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore 117593.
6Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228.
7Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228.
8Division of Hepatobiliary and Liver Transplantation Surgery, National University Health System, Singapore 119228.
9Division of Surgical Oncology, National Cancer Centre Singapore, Singapore 169610; Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore 169608; Duke-NUS Medical School, Singapore 169857.
10Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600; The N.1 Institute for Health (N.1), 28 Medical Dr, Singapore 117456.
11Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Singapore 117594. Electronic address: polly_chen@nus.edu.sg.
Abstract
Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3’end of exon 12. Chemically modified antisense oligonucleotides (ASOs) which target the editing region of AZIN1 caused a substantial exon 11 skipping; while ECS-targeting ASOs effectively abolish AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2′-O-methyl (2′-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.
Keywords: A-to-I RNA editing; ADAR1; AZIN1; Cancer; RNA therapeutics; antisense oligonucleotides.
Copyright © 2021. Published by Elsevier Inc.
PMID: 33974998 DOI: 10.1016/j.ymthe.2021.05.008