Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer

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...

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Veröffentlicht in:Molecular therapy 2021-11, Vol.29 (11), p.3258-3273
Hauptverfasser: Tay, Daryl Jin Tai, Song, Yangyang, Peng, Boya, Toh, Tan Boon, Hooi, Lissa, Toh, Desiree-Faye Kaixin, Hong, HuiQi, Tang, Sze Jing, Han, Jian, Gan, Wei Liang, Chan, Tim Hon Man, Krishna, Manchugondanahalli S., Patil, Kiran M., Maraswami, Manikantha, Loh, Teck Peng, Dan, Yock Young, Zhou, Lei, Bonney, Glenn Kunnath, Chow, Pierce Kah-Hoe, Chen, Gang, Chow, Edward Kai-Hua, Le, Minh T.N., Chen, Leilei
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Sprache:eng
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Zusammenfassung: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) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished 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. [Display omitted] This work identifies an optimal chemistry for RNA editing inhibition and recognizes the importance of understanding the RNA secondary structure of cancer-associated editing substrates prior to the development of ASO-based RNA editing inhibitors. This oligonucleotide-based antisense therapy may hold great promise for the treatment of cancer.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2021.05.008