The Epitranscriptome of Noncoding RNAs in Cancer

Abstract

The activity of RNA is controlled by different types of post-transcriptional modifications, such as the addition of methyl groups and other chemical and structural changes, that have been recently described in human cells by high-throughput sequencing. Herein, we will discuss how the so-called epitranscriptome is disrupted in cancer and what the contribution of its writers, readers, and erasers to the process of cellular transformation is, particularly focusing on the epigenetic modifications of ncRNAs.Significance: Chemical modifications of RNA play a central role in the control of messenger and ncRNA activity and, thus, are tightly regulated in cells. In this review, we provide insight into how these marks are altered in cancer cells and how this knowledge can be translated to the clinical setting. Cancer Discov; 7(4); 359-68. ©2017 AACR.

Figure 1. Examples of RNA chemical modifications; their writers, readers and erasers; and different effects on the transcript molecule

In the middle, a molecule of RNA with different chemical modifications is shown: addition of a 5′-end cap (cap), 5-methylcytosine (m⁵C), 5-hydroxymethylcytosine (hm⁵C), N6-methyladenosine (m⁶A), N1-methyladenosine (m1A), pseudouridine (ψ), editing (Edit), circularization of RNA (circ) and poly (U) tails (U-Tail). Top, protein(s) associated with each modification: writers (green), readers (orange) and erasers (red), Below, functional consequences of RNA modification. Proteins and RNA chemical marks reported to be involved in tumorigenesis are tagged with a yellow star. ADAR, adenosine deaminase RNA specific represented by ADAR1 and ADAR2; APOBEC, apolipoprotein B mRNA editing enzymes represented by APOBEC3A and APOBEC3B; ALKBH3, alkB homolog 3, alpha-ketoglutarate dependent dioxygenase; ALKBH5, alkB homolog 3, alpha-ketoglutarate dependent dioxygenase; BCDIN3, methylphosphate capping enzyme; CMTR, cap methyltransferases represented by CMTR1 and CMTR2; DKC1, dyskerin pseudouridine synthase 1; DNMT2, DNA methyltransferase-2; FTO, fat mass and obesity associated; methyltransferase-like family represented by METTL3 and METTL14; NUDIX, nudix hydrolases represented by CDP2 and NUDT16; NSUN, NOP2/Sun RNA methyltransferase family; PUS, pseudouridine synthase family; RBPs, RNA Binding Proteins such as HuR and HNRNPA2B1; RNBs, RNase II / RNB family represented by Dis3, Dis3L1 and Dis3L2; RNMT, RNA guanine-7 methyltransferase; TET, tet methylcytosine dioxygenase represented by TET1 and TET2; WTAP, Wilms tumor 1 associated protein; TGS1, trimethylguanosine synthase 1; TUT, terminal uridylyl transferases represented by ZCCHC11 (TUT4), ZCCHC6 (TUT7) and PAPD4 (TUT2); YTHD, YT521-B homology domain-containing proteins composed of the YTHDF family (YTHDF1, YTHDF2, YTHDF3), YTHDC1 and YTHDC2.