The Role of RNA Editing in Cancer Development and Metabolic Disorders

Abstract

Numerous human diseases arise from alterations of genetic information, most notably DNA mutations. Thought to be merely the intermediate between DNA and protein, changes in RNA sequence were an afterthought until the discovery of RNA editing 30 years ago. RNA editing alters RNA sequence without altering the sequence or integrity of genomic DNA. The most common RNA editing events are A-to-I changes mediated by adenosine deaminase acting on RNA (ADAR), and C-to-U editing mediated by apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1). Both A-to-I and C-to-U editing were first identified in the context of embryonic development and physiological homeostasis. The role of RNA editing in human disease has only recently started to be understood. In this review, the impact of RNA editing on the development of cancer and metabolic disorders will be examined. Distinctive functions of each RNA editase that regulate either A-to-I or C-to-U editing will be highlighted in addition to pointing out important regulatory mechanisms governing these processes. The potential of developing novel therapeutic approaches through intervention of RNA editing will be explored. As the role of RNA editing in human disease is elucidated, the clinical utility of RNA editing targeted therapies will be needed. This review aims to serve as a bridge of information between past findings and future directions of RNA editing in the context of cancer and metabolic disease.

Keywords: ADAR; APOBEC1; RNA editing; cancer; metabolic disease.

Figure 1

RNA editing leads to functional consequences through multiple mechanisms. RNA editases (ADAR1, ADAR2, ADAR3, and APOBECs in this review) regulate their targets through multiple mechanisms, including altering mRNA sequences in exons to change amino acid sequences (protein recoding; red arrows), changing splicing patterns of pre-mRNA to create novel products (alternative splicing; orange arrows), influencing miRNA specificity by altering seed sequences of miRNAs or sequences of miRNA targeting sites (miRNA specificity; green arrows), and directly impacting the stability of edited RNAs (RNA stability; magenta arrows). X represents a RNA base targeted by RNA editases (Adenosine for ADARs; Cytidine or Guanosine for APOBECs), and Y represents the resultant RNA base after the editing (Inosine for ADARs; Uridine or Adenosine for APOBECs). The hairpin structure in the mRNA represents Alu repeat elements that are frequently targeted by RNA editases. UTR, untranslated region. The figure was created with BioRender.

Figure 2

ADAR1-mediated RNA editing in cancer development. The color of the first arrow in each pathway indicates the mechanism (refer to Figure 1) by which ADAR1 regulates its direct targets, depicted in pink icons or shapes. Dashed lines indicate suggested/unproven functions/relationships. Additional activators and inhibitors of specific pathway steps are depicted in red and yellow rounded rectangles, respectively. Specific diseases and phenotypes/functions affected by ADAR1-mediated RNA editing are only labeled in the first appearance (ex. proliferation…etc). HCC, hepatocellular carcinoma; ESCC, esophageal squamous cell carcinoma; CRC, colorectal cancer; BC, breast cancer; CC, cervical cancer; OC, ovarian cancer; MM, multiple myeloma; MB, medulloblastoma; BCC, basal cell carcinoma; CML, chronic myeloid leukemia; PC, prostate cancer; LUAD, lung adenocarcinoma; KC, kidney cancer; BLC, bladder cancer. The figure was created with BioRender.

Figure 3

ADAR2-mediated RNA editing in cancer development. The color of the first arrow in each pathway indicates the mechanism (refer to Figure 1) by which ADAR2 regulates its direct targets, depicted in pink icons or shapes. Dashed lines indicate suggested/unproven functions/relationships. Specific diseases and phenotypes/functions affected by ADAR2-mediated RNA editing are only labeled in the first appearance (ex. brain cancer). HCC, hepatocellular carcinoma; ESCC, esophageal squamous cell carcinoma; CRC, colorectal cancer. The figure was created with BioRender.

Figure 4

APOBECs-mediated RNA editing in cancer development. The color of the first arrow in each pathway indicates the mechanism (refer to Figure 1) by which APOBECs regulates its direct targets, depicted in pink shapes. Dashed lines indicate suggested/unproven functions/relationships. CRC, colorectal cancer; PNST, peripheral nerve-sheath tumor; AML, acute myeloid leukemia. The figure was created with BioRender.

Figure 5

ADAR1-mediated RNA editing in metabolic disorders. The color of the first arrow in each pathway indicates the mechanism (refer to Figure 1) by which ADAR1 regulates its direct targets, depicted in pink shapes. Additional activators of specific pathway steps are depicted in red rounded rectangles. Specific diseases and phenotypes/functions affected by ADAR1-mediated RNA editing are only labeled in the first appearance (ex. CVD). CVD, cardiovascular disease; SMC, smooth muscle cell. The figure was created with BioRender.

Figure 6

ADAR2-mediated RNA editing in metabolic disorders. The color of the first arrow in each pathway indicates the mechanism (refer to Figure 1) by which ADAR2 regulates its direct targets, depicted in pink icons or shapes. Dashed lines indicate suggested/unproven functions/relationships. Additional activators and inhibitors of specific pathway steps are depicted in red and yellow rounded rectangles, respectively. CVD, cardiovascular disease. The figure was created with BioRender.

Figure 7

APOBEC1-mediated RNA editing in metabolic disorders. The color of the first arrow in each pathway indicates the mechanism (refer to Figure 1) by which APOBEC1 regulates its direct targets, depicted in pink shapes. Additional activators of specific pathway steps are depicted in red rounded rectangles. Gray arrows point to ApoB-associated secondary functions. ER, endoplasmic reticulum; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. The figure was created with BioRender.