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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

2 Scopus Citations
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Author(s)

  • Daryl Jin Tai Tay
  • Yangyang Song
  • Tan Boon Toh
  • Lissa Hooi
  • Desiree-Faye Kaixin Toh
  • HuiQi Hong
  • Sze Jing Tang
  • Jian Han
  • Wei Liang Gan
  • Tim Hon Man Chan
  • Manchugondanahalli S. Krishna
  • Kiran M. Patil
  • Manikantha Maraswami
  • Teck Peng Loh
  • Yock Young Dan
  • Lei Zhou
  • Glenn Kunnath Bonney
  • Pierce Kah-Hoe Chow
  • Gang Chen
  • Edward Kai-Hua Chow
  • Leilei Chen

Detail(s)

Original languageEnglish
Pages (from-to)3258-3273
Journal / PublicationMolecular Therapy
Volume29
Issue number11
Online published8 May 2021
Publication statusPublished - Nov 2021

Link(s)

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) 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.

Research Area(s)

  • A-to-I RNA editing, ADAR1, antisense oligonucleotides, AZIN1, cancer, RNA editing inhibtion, RNA therapeutics

Citation Format(s)

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

In: Molecular Therapy, Vol. 29, No. 11, 11.2021, p. 3258-3273.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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