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Title: Targeting RNA Editing of Antizyme Inhibitor 1: a Potential Oligonucleotide-Based Antisense Therapy for Cancer.
Authors: 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 
Chen, Leilei 
Keywords: A-to-I RNA editing
RNA therapeutics
antisense oligonucleotides
Issue Date: 8-May-2021
Publisher: Elsevier BV
Citation: 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, Chen, Leilei (2021-05-08). Targeting RNA Editing of Antizyme Inhibitor 1: a Potential Oligonucleotide-Based Antisense Therapy for Cancer.. Mol Ther. ScholarBank@NUS Repository.
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.
Source Title: Mol Ther
ISSN: 15250016
DOI: 10.1016/j.ymthe.2021.05.008
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