TY - JOUR
T1 - Targeting RNA editing of antizyme inhibitor 1
T2 - A potential oligonucleotide-based antisense therapy for cancer
AU - Tay, Daryl Jin Tai
AU - Song, Yangyang
AU - Peng, Boya
AU - Toh, Tan Boon
AU - Hooi, Lissa
AU - Toh, Desiree Faye Kaixin
AU - Hong, Hui Qi
AU - Tang, Sze Jing
AU - Han, Jian
AU - Gan, Wei Liang
AU - Chan, Tim Hon Man
AU - Krishna, Manchugondanahalli S.
AU - Patil, Kiran M.
AU - Maraswami, Manikantha
AU - Loh, Teck Peng
AU - Dan, Yock Young
AU - Zhou, Lei
AU - Bonney, Glenn Kunnath
AU - Chow, Pierce Kah Hoe
AU - Chen, Gang
AU - Chow, Edward Kai Hua
AU - Le, Minh T.N.
AU - Chen, Leilei
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/11/3
Y1 - 2021/11/3
N2 - 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.
AB - 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.
KW - A-to-I RNA editing
KW - ADAR1
KW - antisense oligonucleotides
KW - AZIN1
KW - cancer
KW - RNA editing inhibtion
KW - RNA therapeutics
UR - http://www.scopus.com/inward/record.url?scp=85114671007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114671007&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2021.05.008
DO - 10.1016/j.ymthe.2021.05.008
M3 - Article
C2 - 33974998
AN - SCOPUS:85114671007
SN - 1525-0016
VL - 29
SP - 3258
EP - 3273
JO - Molecular Therapy
JF - Molecular Therapy
IS - 11
ER -
