Abstract
BackgroundWhole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances in the understanding of ADAR function in breast cancer, ADAR RNA editing functional consequences are not fully addressed.ResultsWe characterized A to G(I) mRNA editing in 81 breast cell lines, showing increased editing at 3′UTR and exonic regions in breast cancer cells compared to immortalized non-malignant cell lines. In addition, tumors from the BRCA TCGA cohort show a 24% increase in editing over normal breast samples when looking at 571 well-characterized UTRs targeted by ADAR1. Basal-like subtype breast cancer patients with high level of ADAR1 mRNA expression shows a worse clinical outcome and increased editing in their 3′UTRs. Interestingly, editing was particularly increased in the 3′UTRs of ATM, GINS4 and POLH transcripts in tumors, which correlated with their mRNA expression. We confirmed the role of ADAR1 in this regulation using a shRNA in a breast cancer cell line (ZR-75-1).ConclusionsAltogether, these results revealed a significant association between the mRNA editing in genes related to cancer-relevant pathways and clinical outcomes, suggesting an important role of ADAR1 expression and function in breast cancer.
Highlights
Whole transcriptome ribonucleic acid (RNA) variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolu‐ tion
ADAR1 expression and activity in breast cell lines We analyzed the transcriptomes from 81 breast cell lines that were publicly available [16], in order to characterize ADAR1 activity
RNA editing is not uniformly distributed along the transcripts, showing a large number of edited sites at intronic and 3′untranslated regions (UTRs) regions [4, 19, 20], we found a large number of edited sites at those regions (Fig. 1c), where the median number of editing sites for immortalized non-malignant cell lines (n = 3) was 3501 and for breast cancer (BC) cells (n = 78) was 4053 A to G(I) sites, not finding significant differences in the total number of edited sites between the immortalized and BC cells (p < 0.2043, Additional file 2: Figure S1A)
Summary
Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolu‐ tion. The main form of RNA editing is the hydrolytic deamination of adenosine, which converts this nucleoside to inosine, catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes [1]. Several studies have reported alterations of ADAR1 activity in cancer, where edited sites in coding regions have been associated with cancer progression [2, 3]. Recent studies have revealed key functional consequences of editing function on UTRs, where ADAR1 activity has been implicated mRNA stability, transcriptome variability and mRNA expression changes, by altering the canonical RNA–RNA and RNA–protein interactions of its targets [4, 5]. Genome-wide studies have revealed that a large proportion of the transcriptome can be modified by these editing enzymes [4, 6,7,8]. Regions enriched in A-to-G(I) edited sites are mainly located in intronic and UTRs of the transcript, whereas a limited number of edited sites are located in coding exons leading to non-synonymous changes [5, 9]
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