RNA Editing in Pathogenesis of Cancer

Abstract

Several adenosine or cytidine deaminase enzymes deaminate transcript sequences in a cell type or environment-dependent manner by a programmed process called RNA editing. RNA editing enzymes catalyze A>I or C>U transcript alterations and have the potential to change protein coding sequences. In this brief review, we highlight some recent work that shows aberrant patterns of RNA editing in cancer. Transcriptome sequencing studies reveal increased or decreased global RNA editing levels depending on the tumor type. Altered RNA editing in cancer cells may provide a selective advantage for tumor growth and resistance to apoptosis. RNA editing may promote cancer by dynamically recoding oncogenic genes, regulating oncogenic gene expression by noncoding RNA and miRNA editing, or by transcriptome scale changes in RNA editing levels that may affect innate immune signaling. Although RNA editing markedly increases complexity of the cancer cell transcriptomes, cancer-specific recoding RNA editing events have yet to be discovered. Epitranscriptomic changes by RNA editing in cancer represent a novel mechanism contributing to sequence diversity independently of DNA mutations. Therefore, RNA editing studies should complement genome sequence data to understand the full impact of nucleic acid sequence alterations in cancer. .

Pathogenic diversity of RNA variants and RNA variation-associated factors in cancer development

“…APOBEC3A, another site-specific C-to-U editing enzyme, showed editing functions after specific stimulation in monocytes and macrophages 24 . In contrast to those edited by ADARs, most targets edited by APO-BEC3A are very site-specific and often contain coding regions, resulting in missense/nonsense alterations 25 . Whether other APOBECs, including APOBEC2 APO-BEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APO-BEC3H, and APOBEC4, also edit cellular RNAs in specific physiological circumstances is unknown 25 .…”

“…In contrast to those edited by ADARs, most targets edited by APO-BEC3A are very site-specific and often contain coding regions, resulting in missense/nonsense alterations 25 . Whether other APOBECs, including APOBEC2 APO-BEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APO-BEC3H, and APOBEC4, also edit cellular RNAs in specific physiological circumstances is unknown 25 . While some APOBEC3 proteins deaminate viral genetic substances or cancer genomes, the cytidine deaminase functions of these enzymes under normal physiologic conditions have not been demonstrated 26 .…”

Interaction of transforming growth factor‐β‐Smads/microRNA‐362‐3p/CD82 mediated by M2 macrophages promotes the process of epithelial‐mesenchymal transition in hepatocellular carcinoma cells

“…MicroRNAs (miRNAs) are a class of endogenous small (approximately 15‐25 nucleotides in length) noncoding RNAs that can regulate gene expression by binding to the 3′‐UTR. MicroRNAs are involved in several cellular functions, including proliferation, differentiation, and death . Recent studies have revealed that in response to microenvironmental signals, miRNAs regulate macrophage polarization by modulating transcription factors, that induce expression of M1 (miR‐21, miR‐27a/b, miR‐130a/b, and miR‐155) and M2 (miR‐125a/b, miR‐146a/b, miR‐124, miR‐181a, and let‐7c) …”

Widespread cis-regulation of RNA-editing in a large mammal

“…Depending on the location of edits within the pre-mRNA transcript, the potential consequences of RNA editing can include changes to the coding sequence, the creation or destruction of splice sites (Nishikura, 2010), triggering of nuclear retention mechanisms of edited transcripts (Zhang and Carmichael, 2001;Prasanth et al, 2005), or the creation or destruction of miRNA binding sites within the 3 -UTR (Liang and Landweber, 2007;Wang et al, 2013). These changes in turn can affect gene expression, either as part of normal regulation (Goldstein et al, 2017), in a pathogenic context such as cancer (Zhang et al, 2016;Baysal et al, 2017), or as a mechanism to regulate alternative splicing (Solomon et al, 2013).…”