1. Targeting RNA Editing of Antizyme Inhibitor1: a Potential Oligonucleotide-Based Antisense Therapy for Cancer
- Author
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Tai Tay, Daryl Jin, Song, Yangyang, Peng, Boya, Toh, Tan Boon, Hooi, Lissa, Kaixin Toh, Desiree-Faye, Hong, HuiQi, Tang, Sze Jing, Han, Jian, Gan, Wei Liang, Man Chan, Tim Hon, Krishna, Manchugondanahalli S., Patil, Kiran M., Maraswami, Manikantha, Loh, Teck Peng, Dan, Yock Young, Zhou, Lei, Bonney, Glenn Kunnath, Kah-Hoe Chow, Pierce, Chen, Gang, Kai-Hua Chow, Edward, Le, Minh TN., and Chen, Leilei
- 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 AZIN1caused a substantial exon 11 skipping; while ECS-targeting ASOs effectively abolish AZIN1editing 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 vitroand 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.
- Published
- 2021
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