Altered RNA editing in 3′ UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors

Abstract

RNA editing is a molecular event that alters specific nucleotides in RNA post-transcriptionally. RNA editing has the potential to impact a variety of cellular processes and is implicated in diseases such as cancer. Yet, the precise mechanisms by which RNA editing controls cellular processes are poorly understood. Here, we characterize sequences altered by RNA editing in patient samples from lymphoma, neuroblastoma and head and neck cancers. We show that A-to-I RNA editing sites are highly conserved across samples of the same tissue type and that most editing sites identified in tumors are also detectable in normal tissues. Next, we identify the significant changes in editing levels of known sites between tumor and paired “normal” tissues across 14 cancer types (627 pairs) from The Cancer Genome Atlas project and show that the complexity of RNA editing regulation cannot be captured by the activity of ADAR family genes alone. Our pan-cancer analysis confirms previous results on individual tumor types and suggests that changes of RNA editing levels in coding and 3′UTR regions could be a general mechanism to promote tumor growth. We also propose a model explaining how altered RNA editing levels affect microRNA-mediated post-transcriptional regulation of oncogenes and tumor-suppressors.

Dynamic regulation of RNA editing in human brain development and disease

“…We provide some possibilities for how this could occur, such as amino acid changes in functional domains or perturbation of miRNA-binding potential. In fact, previous studies show that A-to-I editing regulates specific RNAs through trafficking 47 or disrupting miRNA-binding 48,49 , as well as through amino acid r e S O u r C e changes. Further studies on molecular mechanisms are necessary to fully appreciate their functional importance.…”

RNA editing-dependent epitranscriptome diversity in cancer stem cells

“…Although the significance of hyperediting of 3′-UTR Alu elements remains largely unknown in cancer biology, several lines of evidence suggest diverse roles, including nuclear retention by the inosine-specific RBP, non-POU domain-containing, octamer binding (NONO, also known as p54 nrb ) 75 , shortening of the 3′-UTR by the inosine-selective nuclease SND1 (REF. 76) and interference with miRNA accessibility 77,78 .…”

miR-21 enhances cardiac fibrotic remodeling and fibroblast proliferation via CADM1/STAT3 pathway

“…miRs can post-transcriptionally silence protein expression either by binding to complementary target mRNAs and degrading these mRNAs, or by inhibiting mRNAs translating into proteins [6]. miRs are emerging as important regulators in participate in cell proliferation, differentiation, and apoptosis [7]. The effect of miR-21 on cardiac fibrosis has been well established [8, 9].…”