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; 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 Vuong; Chen, Leilei

doi:10.1016/j.ymthe.2021.05.008

Cited by 16 publications

(12 citation statements)

References 54 publications

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“…Pin1 is also known to facilitate multiple cancer-driving processes [ 115 ], supporting the prediction of these compounds as potential anti-cancer molecules. Aberrant A-to-I RNA editing has been shown to be implicated in cancers [ 86 , 116 ]. DAP3, which is an ADAR2 inhibitor, has been reported to affect editing targets involved in cancer-related signaling pathways and processes [ 86 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

Broni

Striegel

Ashley

et al. 2023

IJMS

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Altered RNA editing has been linked to several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability, in addition to depression, schizophrenia, some cancers, viral infections and autoimmune disorders. The human ADAR2 is a potential therapeutic target for managing these various disorders due to its crucial role in adenosine to inosine editing. This study applied consensus scoring to rank potential ADAR2 inhibitors after performing molecular docking with AutoDock Vina and Glide (Maestro), using a library of 35,161 compounds obtained from traditional Chinese medicine. A total of 47 compounds were predicted to be good binders of the human ADAR2 and had insignificant toxicity concerns. Molecular dynamics (MD) simulations, including the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) procedure, also emphasized the binding of the shortlisted compounds. The potential compounds had plausible binding free energies ranging from −81.304 to −1068.26 kJ/mol from the MM/PBSA calculations. ZINC000085511995, a naphthoquinone had more negative binding free energy (−1068.26 kJ/mol) than inositol hexakisphosphate (IHP) [−873.873 kJ/mol], an agonist and a strong binder of ADAR2. The potential displacement of IHP by ZINC000085511995 in the IHP binding site of ADAR2 could be explored for possible deactivation of ADAR2. Bayesian-based biological activity prediction corroborates the neuropharmacological, antineoplastic and antiviral activity of the potential lead compounds. All the potential lead compounds, except ZINC000014612330 and ZINC000013462928, were predicted to be inhibitors of various deaminases. The potential lead compounds also had probability of activity (Pa) > 0.442 and probability of inactivity (Pi) < 0.116 values for treating acute neurologic disorders, except for ZINC000085996580 and ZINC000013462928. Pursuing these compounds for their anti-ADAR2 activities holds a promising future, especially against neurological disorders, some cancers and viral infections caused by RNA viruses. Molecular interaction, hydrogen bond and per-residue decomposition analyses predicted Arg400, Arg401, Lys519, Trp687, Glu689, and Lys690 as hot-spot residues in the ADAR2 IHP binding site. Most of the top compounds were observed to have naphthoquinone, indole, furanocoumarin or benzofuran moieties. Serotonin and tryptophan, which are beneficial in digestive regulation, improving sleep cycle and mood, are indole derivatives. These chemical series may have the potential to treat neurological disorders, prion diseases, some cancers, specific viral infections, metabolic disorders and eating disorders through the disruption of ADAR2 pathways. A total of nine potential lead compounds were shortlisted as plausible modulators of ADAR2.

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Section: Resultsmentioning

confidence: 99%

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

Broni

Striegel

Ashley

et al. 2023

IJMS

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“…ASO bind complementary RNA sequences and recruit ribonuclease H for RNA degradation in vitro and in vivo [51][52][53]. Research on targeted therapy using ASO-based technology has developed rapidly, indicating that ASO is a very promising therapeutic strategy in clinical practice [51,52,54]. Here, ASO-MALAT1 greatly reduced the proliferation of HCC tumors in our xenograft model, and BRF2 expression was decreased in tumors.…”

Section: Discussionmentioning

confidence: 72%

MALAT1/ miR-1-3p-mediated BRF2 promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway

Meng

Pan

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and one of the main causes of cancer-related death worldwide. Many studies have shown that abnormal expression of lncRNA plays a crucial role in HCC. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to play a vital role in various tumors. However, the underlying mechanism of MALAT1 in HCC has not been thoroughly elucidated. The expression of MALAT1 were detected by qRT-PCR. Antisense oligonucleotides (ASO)-MALAT1 transfected cells were used to explore the biological effects of MALAT1 by cell CCK-8, colony formation, transwell, wound healing, and flow cytometry analysis. Western blotting was performed to measure PI3K/Akt and apoptosis-related protein levels. Dual-luciferase reporter assay was performed to verify the relationship between MALAT1 and its specific targets. We found that MALAT1 was upregulated, and MALAT1 knockdown inhibited migration and invasion, and it induced apoptosis in vitro and in vivo. Further studies demonstrated that MALAT1 positively regulated the expression of transcription factor II B‑related factor 2 (BRF2) which was associated with clinical index and poor prognosis. Mechanistically, MALAT1 was found to act as a competitive endogenous RNA to sponge hsa-miR-1-3p, which upregulated BRF2. Knockdown of BRF2 inhibited the progression of HCC by the LKB1/AMPK pathway. Overexpression of BRF2 reversed the inhibitory effect of MALAT1 knockdown. Our results demonstrate a novel MALAT1/miR-1-3p/BRF2/LKB1/AMPK regulatory axis in HCC, which may provide new molecular therapeutic targets for HCC in the future.

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“…The copyright holder for this preprint this version posted April 17, 2023. ; https://doi.org/10.1101/2023.04.17.537126 doi: bioRxiv preprint edited in the nucleus, one group reported that nuclear ADAR1 p110 was the responsible enzyme (55,59). Furthermore, the same group recently reported that AZIN1 RNA editing required a dsRNA structure formed between Ex11 and Ex12 in the presence of In11 in the nucleus (60). In contrast, we found that editing levels at two sites of Azin1 mRNA were not reduced in Adar1 p110 -/-/Adar2 -/mice ( 14), which suggests that ADAR1 150 is responsible for Azin1 RNA editing in vivo.…”

Section: Discussionmentioning

confidence: 99%

RNA editing of AZIN1 coding sites is catalyzed by ADAR1 p150 after splicing

Xing

Nakahama

et al. 2023

Preprint

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Adenosine-to-inosine RNA editing is catalyzed by nuclear ADAR1 p110 and ADAR2, and cytoplasmic ADAR1 p150 in mammals, all of which recognize double-stranded RNAs (dsRNAs) as targets. Although its frequency is quite rare, RNA editing occurs in coding regions, which alters protein functions by exchanging amino acid sequences, and is therefore physiologically significant. In general, such coding sites are edited by ADAR1 p110 and ADAR2 prior to splicing, given that the corresponding exon forms a dsRNA structure with an adjacent intron. We previously found that RNA editing at two coding sites of antizyme inhibitor 1 (AZIN1) is sustained in Adar1 p110/Aadr2 double knockout mice. However, the molecular mechanisms underlying RNA editing of AZIN1 remain unknown. Here, we showed that Azin1 editing levels were increased upon type I interferon treatment, which activated Adar1 p150 transcription, in mouse Raw264.7 cells. Azin1 RNA editing was observed in mature mRNA but not precursor mRNA. Furthermore, we revealed that the two coding sites were editable only by ADAR1 p150 in both mouse Raw264.7 and human HEK293T cells. This unique editing was achieved by forming a dsRNA structure with a downstream exon after splicing and the intervening intron suppressed RNA editing. Therefore, deletion of a nuclear export signal from ADAR1 p150, shifting its localization to the nucleus, decreased Azin1 editing levels. Finally, we demonstrated that Azin1 RNA editing was completely absent in Adar1 p150 knockout mice. Thus, these findings indicate that RNA editing of AZIN1 coding sites is exceptionally catalyzed by ADAR1 p150 after splicing.

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

Cited by 16 publications

References 54 publications

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

MALAT1/ miR-1-3p-mediated BRF2 promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway

RNA editing of AZIN1 coding sites is catalyzed by ADAR1 p150 after splicing

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