Global Transcriptome Analysis of RNA Abundance Regulation by ADAR in Lung Adenocarcinoma

Abstract

Despite tremendous advances in targeted therapies against lung adenocarcinoma, the majority of patients do not benefit from personalized treatments. A deeper understanding of potential therapeutic targets is crucial to increase the survival of patients. One promising target, ADAR, is amplified in 13% of lung adenocarcinomas and in-vitro studies have demonstrated the potential of its therapeutic inhibition to inhibit tumor growth. ADAR edits millions of adenosines to inosines within the transcriptome, and while previous studies of ADAR in cancer have solely focused on protein-coding edits, > 99% of edits occur in non-protein coding regions. Here, we develop a pipeline to discover the regulatory potential of RNA editing sites across the entire transcriptome and apply it to lung adenocarcinoma tumors from The Cancer Genome Atlas. This method predicts that 1413 genes contain regulatory edits, predominantly in non-coding regions. Genes with the largest numbers of regulatory edits are enriched in both apoptotic and innate immune pathways, providing a link between these known functions of ADAR and its role in cancer. We further show that despite a positive association between ADAR RNA expression and apoptotic and immune pathways, ADAR copy number is negatively associated with apoptosis and several immune cell types' signatures.

Widespread cis-regulation of RNA editing in a large mammal

“…A broadly negative relationship between editing and transcript abundance also fits with a mechanism by which mRNA expression is controlled through preferential retention of edited transcripts in the nucleus (Zhang and Carmichael 2001;Prasanth et al 2005), or a mechanism whereby mature mRNA abundance is reduced due to altered splicing mediated by RNA editing (Fei et al 2016). We note, however, that these results are different to those reported recently by Sharpnack et al (2018), who observed a positive association between RNA editing and gene expression, acknowledging that this was in the context of lung adenocarcinoma.…”

“…Given the observation of widespread editing across diverse mammary transcripts, we wondered what physiological effects might be attributable to these modifications. Since editing has previously been proposed as a mechanism to modulate gene expression through microRNA-based mechanisms (Liang and Landweber 2007;Wang et al 2013;Brümmer et al 2017), through nuclear retention (Zhang and Carmichael 2001;Prasanth et al 2005), or by preventing activation of the MDA5-MAVS interferon response (Sharpnack et al 2018), we looked at the relation-ship between Φ-values and transcript abundance by calculating Pearson correlation coefficients for each implicated gene. For this analysis, we were particularly interested in the impacts on mRNA, so to best represent spliced transcripts, transcript abundance was quantified using reads that either mapped wholly within exons, or mapped across exon-exon boundaries (see Materials and Methods).…”

“3G” Trial: An RNA Editing Signature for Guiding Gastric Cancer Chemotherapy

“…These sites include previously reported hotspots (frequently edited) with pathogenic role (e.g. EIF2AK2, MAVS, GATC, CTSS, METTL7A) 34,42,[44][45][46] as well as novel sites reported here for the first time (e.g.…”

Non-Coding RNAs in Lung Tumor Initiation and Progression

“…Previous studies have demonstrated that ADAR1 inhibits miRNA processing globally through forming ADAR1/Dicer complex via the RNA interference machinery [158]. Although most ADAR editing occurs in non-coding regions in lung cancer, few studies have shown the crosstalk between ADAR and non-coding RNAs [159]. Anadon et al have demonstrated that ADAR1 gene amplification in NSCLC promotes tumor growth via enhanced A-to-I editing of RNA transcripts including miR-381 [160].…”