RNA editing in cancer impacts mRNA abundance in immune response pathways

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.

RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways

“…Furthermore, EIF2AK2 exhibited positive expression-editing correlations in GBM ( Figure 7 d for TCGA and Figure 7 e for CGGA) and IDH-MUT gliomas ( Figure S6 ). This agrees with the finding that editing of the 3′UTR of EIF2AK2 increased endogenous EIF2AK2 mRNA abundance in non-small cell lung carcinoma [ 27 ]. Collectively, RNA editing of EIF2AK2 may function as a sex-dependent mediator of glioma progression through regulating the mRNA abundance.…”

“…The observation that most DESs located in 3′UTRs prompted us to investigate the capacity of editing to modulate mRNA abundance. To date, three studies have investigated the regulatory potential of RNA editing on the transcriptome-wide scale [ 27 , 28 , 29 ]. Sharpnack et al showed that 1413 genes displayed correlation between editing level and gene expression in lung adenocarcinoma [ 29 ], and Gu et al discovered editing sites that could affect gene expression in four cancer types [ 28 ].…”

“…Particularly, these studies mostly focused on editing events on the coding regions [ 16 , 25 , 26 ], which represent less than 1% of the identified editing sites [ 15 ]. Although a few studies have investigated the regulatory potential of noncoding editing events on the transcriptome-wide scale [ 27 , 28 , 29 ], the regulatory role of RNA editing during glioma progression remains unclear.…”

Suppression of RNA editing by miR-17 inhibits the stemness of melanoma stem cells

“…RNA editing is involved in tumorigenesis. 36 However, the underlying mechanism of miRNA-regulated RNA editing in cancer stem cells has not been extensively explored. In this study, the cumulative results showed that miR-17 downregulated ADAR2 to suppress DOCK2 mRNA editing in melanoma stem cells.…”

Targeting ADAR1 with a Novel Small-Molecule for the Treatment of Prostate Cancer

“…Several studies have analyzed RNA editing pro le in cancer from high-throughput whole transcriptome RNA-seq data in public databases, showing that A-to-G editing levels are higher in most tumors rather than in the matched normal tissues (28-31), including prostate cancer. Recently, Chan and colleagues reported that ve types of cancers have hyperediting patterns in the mesenchymal (M) phenotypes rather than in the epithelial (E) phenotypes, including prostate cancer (55). However, the precise molecular mechanism through which ADAR1-mediated A-to-G editing leading to prostate carcinogenesis and metastasis was not fully explored in these studies.…”