RNA editing in cancer impacts mRNA abundance in immune response pathways
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RESEARCH
Open Access
RNA editing in cancer impacts mRNA abundance in immune response pathways Tracey W. Chan1†, Ting Fu2†, Jae Hoon Bahn3, Hyun-Ik Jun3, Jae-Hyung Lee3,4, Giovanni Quinones-Valdez5, Chonghui Cheng6 and Xinshu Xiao1,2,3,7,8,9* * Correspondence: [email protected] † Tracey Chan and Ting Fu contributed equally to this work. 1 Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA 2 Molecular, Cellular and Integrative Physiology Interdepartmental Program, UCLA, Los Angeles, CA, USA Full list of author information is available at the end of the article
Abstract Background: RNA editing generates modifications to the RNA sequences, thereby increasing protein diversity and shaping various layers of gene regulation. Recent studies have revealed global shifts in editing levels across many cancer types, as well as a few specific mechanisms implicating individual sites in tumorigenesis or metastasis. However, most tumor-associated sites, predominantly in noncoding regions, have unknown functional relevance. Results: Here, we carry out integrative analysis of RNA editing profiles between epithelial and mesenchymal tumors, since epithelial-mesenchymal transition is a key paradigm for metastasis. We identify distinct editing patterns between epithelial and mesenchymal tumors in seven cancer types using TCGA data, an observation further supported by single-cell RNA sequencing data and ADAR perturbation experiments in cell culture. Through computational analyses and experimental validations, we show that differential editing sites between epithelial and mesenchymal phenotypes function by regulating mRNA abundance of their respective genes. Our analysis of RNA-binding proteins reveals ILF3 as a potential regulator of this process, supported by experimental validations. Consistent with the known roles of ILF3 in immune response, epithelial-mesenchymal differential editing sites are enriched in genes involved in immune and viral processes. The strongest target of editing-dependent ILF3 regulation is the transcript encoding PKR, a crucial player in immune and viral response. Conclusions: Our study reports widespread differences in RNA editing between epithelial and mesenchymal tumors and a novel mechanism of editing-dependent regulation of mRNA abundance. It reveals the broad impact of RNA editing in cancer and its relevance to cancer-related immune pathways.
Introduction RNA editing, the modification of specific nucleotides in RNA sequences, expands diversity in proteins and gene regulatory mechanisms [1, 2]. The most frequent type of RNA editing in human cells is A-to-I editing, which refers to the deamination of adenosine (A) to inosine (I) and is catalyzed by the adenosine deaminases acting on RNA (ADAR) family of enzymes [3]. Three ADAR genes are encoded in the human genome, © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as
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