Cancer Letters 474 (2020) 127–137 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Writers, readers and erasers of RNA modifications in cancer T a,1 a,1 a,b,c,d,∗ Rosaura Esteve-Puig , Alberto Bueno-Costa , Manel Esteller a Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain b Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain c Institucio Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Catalonia, Spain d Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain A R T I C LE I N FO A B S T R A C T Keywords: Although cancer was originally considered a disease driven only by genetic mutations, it has now been proven Epigenetics that it is also an epigenetic disease driven by DNA hypermethylation-associated silencing of tumor suppressor RNA modifications genes and aberrant histone modifications. Very recently, a third component has emerged: the so-called epi- RNA-Modifying enzymes transcriptome understood as the chemical modifications of RNA that regulate and alter the activity of RNA RNA-Editing molecules. In this regard, the study of genetic and epigenetic disruption of the RNA-modifying proteins is gaining momentum in advancing our understanding of cancer biology. Furthermore, the development of epitran- scriptomic anticancer drugs could lead to new promising and unexpected therapeutic strategies for oncology in the coming years. 1. Introduction epitranscriptome is just the tip of the iceberg [1] and is starting to emerge, revealing the mechanisms and functions of RNA modification Cancer was fundamentally considered a genetic disease. However, it biology. In particular, RNA modifications have a broad spectrum of is not until most recently that it has also been recognized as an epige- functions in RNA metabolism, including RNA processing [2], splicing netic and metabolic disease, beyond genetics. The impairment of me- [3,4], polyadenylation, editing [5], structure [6], stability [7], locali- tabolic programs in cancer has a deep effect on epigenetic regulation, zation, translation initiation [8], and gene expression regulation [9]. which contributes to genomic instability and alters the epigenetic In the past two decades, remarkable advances in high throughput landscape. Improved understanding of the common tumor-promoting technologies, such as the Next-Generation Sequencing (NGS) methods, metabolic preferent pathways in cancer progression and of metabolic genome-wide DNA methylation profiling, proteomics, and metabo- plasticity in cancer drug resistance, have revealed promising ther- lomics, along with the era of collaborations and interdisciplinary re- apeutic targets based on tumor metabolic and epigenetic vulnerabilities search teams, have enabled us to achieve a more complete under- rather than the extreme variation of the genetic profiles of tumours. standing of tumor biology and to accelerate biomedical research. Thus, A limited repertoire of epigenetic modifications in DNA is docu- the integration of cancer multi-omics approaches and datasets is likely mented compared to epitranscriptomic modifications. DNA methylation to reflect the biological complexity of cancer biology (Fig. 1). Moreover, is the best-characterized epigenetic mechanism. It mainly occurs on the discovery of the epitranscriptome revealed another omic layer and a cytosines (5 mC, 5hmC, 5 fC, and 5caC) and is the most abundant and new dimension of gene expression regulation, the study of which is stable epigenetic mark in eukaryotes that is closely involved in gene beginning to elucidate the complex orchestration of the gene expression regulation. programs and the roles of RNA modification pathways in cancer. In contrast, much less is known about the more than 170 distinct Within the last ten years, the field of traditional cancer drug dis- RNA chemical modifications, their roles, and their respective RNA- covery, which has mainly focused on oncogenic drivers, has brought modifying proteins that deposit, remove, and recognize them on the about major advances in clinical oncology. However, in many cases, specific RNA species found. Indeed, the study of the RNA epigenome or patients ultimately acquire cancer drug resistance, which often arises as Abbreviations: RMPs, RNA-Modifying Proteins; NSCLC, Non-Small Cell Lung Cancer; AML, Acute Myeloid Leukemia; NGS, Next-Generation Sequencing; m6A, N6- Methyladenosine; METTL, Methyltransferase-like ∗ Corresponding author. Josep Carreras Leukaemia Research Institute (IJC), Carretera de Can Ruti, Camí de les Escoles s/n, 08916, Badalona, Barcelona, Catalonia, Spain. E-mail address: mesteller@carrerasresearch.org (M. Esteller). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.canlet.2020.01.021 Received 15 November 2019; Received in revised form 9 January 2020; Accepted 21 January 2020 0304-3835/ © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 Fig. 1. Linking “omic” approaches to cancer: seeking a comprehensive picture of tumor biology. Multi-omics from the genome, epigenome, transcriptome, epi- transcriptome, proteome, and epiproteome. a consequence of the epigenetic and metabolic plasticity of cancer cells cofactor to methylate RNA. They are a well-known and diverse group of [10]. Therefore, because little is currently known about the develop- “writers” involved in human diseases such as METTL3 in lymphoid ment of epigenetic cancer drugs, the RNA-modifying proteins could malignancies and NSUN5 in glioblastoma. Recent studies suggest, represent a promising new class of anticancer target for drug discovery, however, that mRNA methylation might require synergy among the to better leverage advances in cancer treatment and to improve patient member proteins of the methyltransferase complexes for efficient RNA outcomes. methylation, which could vary depending on the cellular phenotypes and the disease processes in play [14]. 2. Proteins involved in RNA chemical modifications Many enzymes have been identified as being RNA methyl- transferases, such as METTL, NSUN, TRMT, MePCE, BCDIN3D, The epitranscriptome is characterized by over a hundred chemical ALKBH8, RNMT, and TRMT family of proteins. Examples of non-me- marks on cellular RNAs that regulate the activities of the transcripts thyltransferases are DKC1, NAT10, and TRIT1, which are “writers” for [11]. These RNA modifications are recognized at specific regions of a RNA modifications pseudouridine (Ψ), N4-acetylcytosine, and N6-iso- transcript by “readers” and are catalyzed by effectors capable of de- pentenyladenosine, respectively. positing and removing them [11]. Collectively, these proteins are Fat mass and obesity-associated protein (FTO) was the first RNA known as RNA-modifying proteins (RMPs), in a close analogy to epi- “eraser” discovered in 2011. It was found to demethylate m6A in DNA genetic regulation mediated by modifications of DNA, histones, and and RNA, and the methylation at m6A in RNA proved to be reversible chromatin, known as chromatin-modifying proteins. RMPs fall into and dynamic, leading to the coining of the term epitranscriptome. three groups: “writers”, the enzymes that deposit RNA chemical marks; Another m6A RNA demethylase was subsequently identified, the alpha- “erasers”, the enzymes that remove them; and “readers”, the proteins ketoglutarate-dependent dioxygenase known as alkb homolog 5 that selectively recognize and bind to specific RNA chemical mod- (ALKBH5). In particular, both FTO and ALKBH5 enzymes belong to the ifications. Dysregulation and mutations in RMPs have been associated same ALKBH family. with human diseases [12], including neurological diseases, cancer, Proteins that produce a cellular response by recognizing RNA genetic birth defects, obesity, and infertility. The first RMP identified as modifications are known as RNA “readers”. The YTH domain proteins being involved in human disease was the m6A “eraser” FTO, which was are the most well-studied family of RNA “readers” [15]. They bind to associated with obesity and cancer. m6A-modified mRNA and fulfill several functions: YTHDC1 binds to The deposition of chemical modifications onto RNAs is catalyzed by nascent m6A-methylated mRNA in the nucleus, participating in exon multiprotein writer complexes. The first methyltransferase-like selection during splicing events; YTHDF1 binds to m6A-modified mRNA (METTL) gene family member, METTL3, was identified in 1994 [13]. in the cytoplasm, increasing translation efficiency independent of the METTL3 form a multicomponent methyltransferase complex that m7G cap; on the other hand, YTHDF2 recruits the CCR4-NOT complex transfers a methyl group at the N6 position of the adenosine base (m6A) to the bound mRNA, increasing rate of decay. Other m6A “readers” are in specific RNA transcripts (mRNAs and ncRNAs). Methylation is one of the IGF2BP family of proteins, which increase the stability of the m6A- the most common modifications in RNA. RNA methyltransferase en- methylated mRNAs [16]. And m5C “reader” ALYREF recognizes m5C zymes catalyze methylation via a methyl synthase mechanism using the modification in mRNA, promoting its nucleus-to-cytosol export [17]. ubiquitous methyl donor S-adenosylmethionine (SAM) as a source and Unidirectional and nonreversible RNA-editing mechanisms alter the 128 R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 Table 1 RNA modifications and RNA-modifying proteins related to cancer development.Legend: W: Writer, E: Eraser, R: Reader, TS: Tumor suppressor, Onc: Oncogene. Nt. RNA Modification RNA-modifying proteins Site-specific position & RNA specie Associated Cancer Cancer Ref. A m1A TRMT6 (W) A58 tRNA-Met Gastrointestinal Cancer (Onc) [46] mRNA Gastrointestinal Cancer (Onc) [46] TRMT10C (W) A9 tRNA mitchondrial Gastrointestinal Cancer (Onc) [46] TRMT61A (W) A58 tRNA Gastrointestinal Cancer (Onc) [46] mRNA Gastrointestinal Cancer (Onc) [46] ALKBH1 (E) A58 tRNA Cervix Cancer (Onc) [47] ALKBH3 (E) mRNA (5′UTR near Start Codon) Pancreatic Cancer (Onc) [48] Breast Cancer (Onc) [49] Ovarian Cancer (Onc) [49] A58 tRNA Cervix Cancer (Onc) [50] A ms2i6A CDK5RAP1 (W) A37 tRNA mitochondrial Breast Cancer (Onc) [51] Melanoma (Onc) [52] A i6A TRIT1 (W) A37 tRNA-SelenoCys Lung Cancer (TS) [53] Gastric Cancer [54] A m6A METTL3 (W) mRNA (5′UTR, ORF, 3′UTR) Endometrial Cancer (TS) [24] Glioblastoma (TS) [33] Breast Cancer (Onc) [55] Hepatocarcinoma (Onc) [56] AML (Onc) [33] FTO (E) mRNA Glioblastoma (Onc) [57] Cervix Cancer (Onc) [58] AML (Onc) [38] Melanoma (Onc) [59] Gastric Cancer (Onc) [60] Breast Cancer (Onc) [30] ALKBH5 (E) mRNA Pancreatic Cancer (TS) [61] AML (TS) [32] Glioblastoma (Onc) [62] Breast Cancer (Onc) [63] YTHDC2 (R) mRNA Colorectal Cancer (Onc) [64] YTHDF2 (R) mRNA Pancreatic Cancer (Dual Effect) [65] Hepatocarcinoma (Onc) [66] Prostate Cancer (Onc) [67] C m3C METTL6 (W) C32 tRNA-Ser Breast Cancer (Onc) [68] Lung Cancer (Onc) [69] METTL8 (W) mRNA Hepatocarcinoma (TS) [70] ALKBH1 (E) C32 tRNA Hepatocarcinoma (Onc) [70] C34 tRNA mitochondrial Hepatocarcinoma (Onc) [70] Cervix Cancer (Onc) [47] ALKBH3 (E) C32, C47 tRNA Cervix Cancer [50] C m5C NSUN1 (W) C4447 rRNA-28S Leukemia (Onc) [71] NSUN2 (W) C34, C47, C48, C49, C50 tRNA Ovarian Cancer (TS) [72] Skin Cancer (TS) [73] mRNA Squamous-Cell Carcinoma (Onc) [74] Breast Cancer (Onc) [75] Bladder Cancer (Onc) [25] NSUN3 (W) C34 tRNA mitochondrial Non-Small Cell Lung Cancer [76] NSUN4 (W) C841 rRNA-12S Breast and Prostate Cancer [77] NSUN5 (W) C3782 rRNA-28S Glioblastoma (TS) [26] DNMT2 (W) C38 tRNA-Asp Colorectal Cancer (Onc) [78] C ac4C NAT10 (W) C12 tRNA-Leu/Ser Ovaric Cancer [79] mRNA (ORF) Hepatocarcinoma [80] C1337 rRNA-18S Colorectal Cancer (Onc) [81] G m7Gpp(pN) RNMT (W) mRNA (5′Cap) Breast Cancer (Onc) [82] NUDT16 (E) mRNA (5′Cap) T-ALL (TS) [2] G m7G METTL1 (W) G46 tRNA Hepatocarcinoma [83] miRNA Lung Cancer (TS) [84] BUD23 (W) G1639 rRNA-18S Metastasis in p53+ tumours (Onc) [85] G m2,2G TRMT1 (W) G26 tRNA Breast Cancer [86] G m2G TRMT11 (W) G6, G10, G26 tRNA Prostate Cancer [87] G Q TGT (W) G34 tRNA-Asn/Asp/His/Tyr T-Cell Lymphoma (TS) [88] Colon Cancer (Onc) [89] G yW (and derivatives) TYW2 (W) G37 tRNA-Phe Head and Neck (Onc) [90] Breast Cancer (Onc) [91] U m5U TRMT2A (W) U54 (tRNA) Breast Cancer (TS) [92] U ncm5U ELP3 (W) U34 tRNA-Lys/Gln/Glu Breast Cancer (Onc) [93] U mcm5U ELP3 (W) U34 tRNA-Lys/Gln/Glu Breast Cancer (Onc) [93] ALKBH8 (W) U mcm5s2U CTU1 (W) U34 tRNA-Lys/Gln/Glu Breast Cancer (Onc) [93] Melanoma (Onc) [40] CTU2 (W) Breast Cancer (Onc) [93] Melanoma (Onc) [40] ELP3 (W) Breast Cancer (Onc) [93] ALKBH8 (W) Breast Cancer (Onc) [93] (continued on next page) 129 R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 Table 1 (continued) Nt. RNA Modification RNA-modifying proteins Site-specific position & RNA specie Associated Cancer Cancer Ref. U D DUS2 (W) U20 tRNA Lung Cancer [94] U Ψ DKC1 (W) rRNA (~36 sites in 18S, ~57 sites in 28S) X-Linked Dyskeratosis congenita [95] Prostate Cancer (Onc) [96] Breast Cancer (Onc) [97] Hepatocarcinoma (Onc) [98] Lung Cancer (Onc) [99] Others Nm Fibrillarin (W) rRNA (41 sites in 18S, 67 sites in 28S. Breast Cancer (Onc) [100] U14 and G75 in 5.8S) HENMT1 (W) piRNA Testicular tumours [101] Others m(pN) BCDIN3D (W) miRNA (5′Cap) Breast Cancer (Onc) [102] MePCE (W) 7SK RNA Breast Cancer (Onc) [103] Editing A-to-I ADAR1 (W) mRNA Hepatocarcinoma (Onc) [27] Colorectal Cancer (Onc) [104] Gastric Cancer (Onc) [105] Esophageal Cancer (Onc) [28] Glioblastoma (Onc) [106] Lung Cancer (Onc) [5] miRNA Leukemia (Onc) [107] ADAR2 (W) mRNA Gastric Cancer (Onc) [105] Editing C-to-U APOBEC1 (W) mRNA Hepatocarcinoma (Onc) [108] APOBEC3G (W) mRNA Hepatocarcinoma (Onc) [109] RNA modifications: m1A: 1-methyladenosine, ms2i6A: 2-methylthio-N6-isopentenyl-adenosine, i6A: N6-isopentenyladenosine, m6A: N6-methyladenosine, m3C: 3- methylcytosine, m5C: 5-methylcytosine, ac4C: N4-acetylcytosine, m7Gpp(pN): 7-methylguanosine cap, m7G: 7-methylguanosine internal, m2,2G: N2,N2,-di- methylguanosine, m2G: N2-methylguanosine, Q: queuosine, yW et al.: Wybutosine and derivatives, m5U: 5-methyluridine, ncm5U: 5-carbamoyl-methyluridine, mcm5U: 5-methoxycarbonyl-methyluridine, mcm5s2U: 5-methoxycarbonylmethyl-2-thiouridine, D: dihydrouridine, Ψ: pseudouridine, Nm: 2′-O-Methylnucleotide, m(pN): 5′ phosphate monomethylation, A-to-I: Deamination of Adenosine, C-to-U: Deamination of Cytosine. RNA modifying enzymes: ADAR1-3: Adenosine Deaminase RNA Specific 1–3, ALKBH1/3/5/8: AlkB Homolog 1/3/5/8, APOBEC1/3G: Apolipoprotein B mRNA Editing Enzyme Catalytic Subunits 1/3G, BCDIN3D: BCDIN3 Domain Containing RNA Methyltransferase, BUD23: RRNA Methyltransferase And Ribosome Maturation Factor, CDK5RAP1: CDK5 Regulatory Subunit Associated Protein 1, CMTR1/2: Cap Methyltransferase 1/2, CTU1/2: Cytosolic Thiouridylase Subunit 1/2, DKC1: Dyskerin Pseudouridine Synthase 1, DNMT2: tRNA Aspartic Acid Methyltransferase 1, DUS2: Dihydrouridine Synthases 2, ELP3: Elongator Acetyltransferase Complex Subunit 3, FTO: FTO Alpha-Ketoglutarate Dependent Dioxygenase, HENMT1: HEN Methyltransferase 1, METTL1/2/3/6/8/14/16: Methyltransferase Like-1/2/3/6/8/16, NAT10: N-Acetyltransferase 10, NSUN1-5: NOP2/Sun RNA Methyltransferase 1–5, NUDT16: Nudix Hydrolase 16, RNMT: RNA Guanine-7 Methyltransferase, TGT: Queuine TRNA-Ribosyltransferase Catalytic Subunit 1, TRIT1: tRNA Isopentenyltransferase 1, TRMT1/2A/2B1/5/6/10C/11/61A/61B/112: tRNA Methyltransferase Subunits, TYW2: tRNA-YW Synthesizing Protein 2 Homolog. RNA sequences and lead to changes in the transcriptome brought about cancer researchers. The time is ripe to face the challenge of under- by RNA-editing enzymes that regulate metabolism. Adenosine-to-in- standing and characterizing the mechanisms and roles of RNA-mod- osine (A-to-I) editing, along with pseudouridine and ribose 2′-O-me- ifying enzymes and their respective RNA modifications. thylation, is one of the most common types of RNA modification in eukaryotes. The conversion of A-to-I is a unidirectional and irreversible modification catalyzed by adenosine deaminases such as ADAR and 3.1. RNA modifications linked to cancer ADAT family proteins that act on mRNAs and tRNAs, respectively. A-to- I editing has several cellular implications, such as altering enzymatic Due to technological limitations, studies performed over recent protein activity, alternative splicing and cellular response to stress decades have primarily focused on RNA chemical modifications present conditions as well as regulating the innate immune response and in the most highly abundant RNA species (tRNA and rRNA). At present, modulating miRNA biogenesis and function. Another kind of RNA technological advances in mass spectrometry, transcriptome-wide editing, known as C-to-U editing, is catalyzed by the cytidine deaminase analysis of RNA modifications by NGS technologies, and antibody im- family of proteins known as AADs (AID/APOBEC). munoprecipitation have enabled the study of several RNA modifications In summary, the dynamic RNA changes brought about by RNA- that are present in low-abundance RNA species, such as mRNAs and modifying enzymes modulate RNA metabolism and functions, thereby miRNAs [19]. affecting cell fate and differentiation. These enzymes involve complex The first RNA modifications were identified almost 70 years ago. mechanisms and metabolic conditions. As an example, methyl- Pseudouridine (Ψ) was the first to be found in RNA, particularly in transferase reactions consume 12–13 molecules of ATP (Fig. 3). Thus, yeast tRNA [20]. Pseudouridine is the most abundant nucleotide the high-energy cost of RNA modification pathways indicates that the modification in rRNA and tRNA and is also present in mammalian and RNA-modifying enzymes have important consequences in overall cel- yeast mRNA. It plays a role in RNA folding and secondary structure, lular metabolism, suggesting that they have important roles in the stability and translation, and was the first RNA modification to be progression of several types of human cancer. linked to cancer [21]. As mentioned earlier, over 170 RNA chemical modifications thus far have been found in different organisms, and over 60 RNA modifications 3. RNA-modifying proteins and their respective chemical marks in have been identified in eukaryotes (Modomics database: http:// cancer modomics.genesilico.pl/) [22]. The role of RNA modifications is not only determined by the incorporation, removal or recognition of RNA One of the major discoveries of clinical importance in the field of marks at selective sites on specific nucleotides of a variety RNA mole- epitranscriptomics is the identification of coding and noncoding RNA cules, but also by specific cellular settings, such as cell-context-specific modifications linked to several human diseases, including cancer [18]. and cell-state-dependent patterns. RNA modifications influence a dis- Many RNA-modifying enzymes with crucial roles in human diseases tinct and broad spectrum of functions in RNA metabolism, including have been identified over the past decade, attracting interest from RNA stability, splicing, processing, editing, structure, localization, 130 R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 translation initiation, and gene regulation. Thus, although the existence translational shifts that may lead to cancer progression (summarized in of these modifications is well known, the mechanisms and functions of Table 1 and Fig. 2A). many of them remain largely unknown. Dissecting the functions of RNA There are many other types of RNA modifications related to cancer modifications is challenging because RNA transcripts are diverse progression. However, they are not all described in this review. In brief, (coding and noncoding), highly structured, relatively short-lived with the deposition or removal of RNA modification in various RNA species highly variable half-lives, located in several cellular compartments and regulates a broad spectrum of RNA regulatory processes that results in amplified through transcription (low- or high-abundance RNAs). Ac- the regulation of a specific sets of genes. Thus, the molecular destiny of curate and precise methods are needed to detect and quantify them any given RNA transcript is determined by the context of the RNA alongside integrated multi-omics research for a better understanding of molecule and the RNA effector enzymes in question. The crucial factors their molecular mechanisms and roles. Hence, an exciting new era is that determine RNA modification metabolism are subcellular localiza- emerging to decode the epitranscriptome, a complex layer of RNAs tion of both RNAs and RNA-modifying proteins, the number of tran- decorated with chemical marks (Fig. 1). scripts of specific cellular RNAs, the various types of RNAs, the folding Alteration of RNA modification patterns is well-understood and is and structure of RNAs, RNA-protein interactions, and responses to associated with various human diseases such as cancer [12]. Table 1 stress stimuli such DNA and RNA damage [11]. Remarkably, defects in compiles all the RNA modifications and RNA-modifying enzymes that any of these processes may lead to cancer progression. have, to date, been linked to cancer. One of the most well-studied RNA modifications linked to cancer is 3.2. RNA-modifying enzymes and their RNA modifications associated with N6-methyladenosine (m6A). This modification is reversible and is the cancer most prevalent modified nucleotide found in eukaryotic mRNAs and in low-abundance ncRNA (miRNA), affecting more than 7000 mRNAs in The number of RNA-modifying enzymes is steadily increasing and mammalian cells and exerting many regulatory functions affecting RNA accounts for about 350 enzymes (Modomics database) [22], opening up metabolism; these include increasing turnover of mRNA through new lines of research in the field of epitranscriptomics. Gene amplifi- binding to the reader YTHDF2 (Fig. 2B), promoting mRNA translation cations and mutations of RMPs have been reported in cancer [12], through binding to YTHDF1, promoting exon inclusion during splicing demonstrating that alterations in these enzymes are associated with by binding to YTHDC1, promoting pri-miRNA processing by recruiting tumor initiation and progression, metastasis, and cancer drug re- hnRNPA2B1 and DGRC8, and regulating transcript nuclear export. sistance. Many new functions of m6A are still being discovered. Depending on The examples of RNA-modifying enzymes implicated in cancer are the cancer cell type, m6A can promote or suppress tumorigenesis. On shown and listed in Table 1, containing the RNA modification enzymes the one hand, a high amount of m6A mark promotes the translation of linked to a specific RNA chemical modifications and the related cancer key oncogenic drivers such as MYC, retaining pluripotency attributes types. The most relevant findings of RNA-modifying enzymes are and blocking cell differentiation in Acute Myeloid Leukemia (AML) summarized below with a special focus on “writers” and “erasers”. cells [23], but on the other hand, the low amount of m6A is also as- The gene amplification of RNA-editing enzyme ADAR1 is associated sociated with oncogenic functions, downregulating the expression of with lung [5], liver [27] and esophageal cancers [28], as well as chronic PHLPP2, a negative regulator of AKT, and thereby enhancing tumor- myelogenous leukemia [29]. In particular, ADAR1 promotes lung igenesis in endometrial cancer cells [24]. Thus, the m6A role in cancer cancer through A-to-I editing of coding NEIL1 mRNA and non-coding progression depends entirely on the cell type and mRNA affected. miRNA miR-381 [5]. Another significant RNA modification is 5-methylcytosine (m5C), As an example of RNA “writers” and “erasers”, it has been docu- which is present in many types of RNA, including mRNA, rRNA, tRNA mented that the overexpression of the RNA-modifying enzymes FTO and other types of ncRNA. Similar to the m6A mark, m5C acts as an [30], METTL3 [31], and NSUN2 [26 promotes pathogenesis through oncogene and tumor suppressor. For example, the enrichment of the stabilizing specific sets of mRNAs in breast cancer, AML, and bladder methyl mark m5C in mRNAs of certain oncogenes promotes bladder cancer, respectively (Fig. 3). Furthermore, the loss of ALKBH5 [32] in cancer progression through the stabilization of multiple mRNA tran- AML and METTL3 [33] and NSUN5 [26] in glioblastoma promotes scripts including HDGF and RAB11 [25]. More recently, it was reported disease progression. Additionally, dysregulation of RNA readers also that the loss of m5C mark in the position C3782 of 28S rRNA leads to has implications in cancer progression. For m6A readers, YTHDC2 has glioblastoma progression by epigenetic silencing of NSUN5, associated been implicated in colorectal cancer and YTHDF2 dysregulation is re- with depletion of global protein synthesis and a shift of the translational lated to pancreatic, hepatic, and prostate cancers (Table 1). profile to a more stress-resistant phenotype [26] (Figs. 2C and 3). Paradoxically, some RNA-modifying enzymes might exhibit both Inosine is the product of the enzymatic deamination of adenosine oncogenic and tumor suppressors functions. For instance, m6A me- and is a highly conserved RNA-editing mechanism that changes the thyltransferase METTL3 was reported to have dual roles in cancer, encoded information of RNA, since inosine preferentially pairs with acting as an oncogene in AML, breast, and liver cancers, and as a tumor cytidine instead of thymine. This modification occurs only in double- suppressor in glioblastoma and endometrial cancers. Analogously, stranded regions of mRNA, tRNA, rRNA, and miRNAs. In mRNA, in- ALKBH5 and TGT were identified to have similar dual roles as onco- osine can recode a protein-coding mRNA sequence and alter splice sites, genes and tumor suppressors in different types of cancer, indicating that while in ncRNA, it alters nRNA structure and can thereby alter the the role of RNA-modifying enzymes is cell-type-specific and tissue- capacity to bind to other molecules. Impaired editing of key transcripts context-dependent (see Fig. 2 and Table 1 for more details). Moreover, can lead to certain types of cancer, in which highly edited NEIL1 and some studies focused on understanding the role in cancer of m6A and its miR-381 transcripts enhance the growth of the Non-Small-Cell Lung associated enzymes have unexpectedly indicated that m6A may en- Cancer (NSCLC) A459 cells [5]. hance oncogenesis, yet in other instances may inhibit cell proliferation An important number of RNA modifications related to cancer affect and transformation. In particular, METTL3 as methyltransferase of m6A the wobbling and dangling positions of tRNAs (bases 34 and 37, re- was identified as an oncogene in AML and demonstrated that the spectively). These two positions can harbor many different types of overexpression of wild-type METTL3 inhibits cell differentiation and modifications, which facilitate the decoding of multiple synonymous increases cell growth through its ability to catalyze the deposition of mRNA codons and restrict pairing with non-cognate codons. More m6A and enhance the translational activation of C-MYC, BCL2 and precisely, defects in tRNAs modifications at position 34 (queuosine, PTEN mRNA transcripts in AML cells [31]. However, another study mcm5s2U, m5C, and m3C), and position 37 (wybutosine and deriva- showed that m6A demethylase FTO [34] is highly expressed in certain tives, N6-isopentenyladenosine, and ms2i6A), are related with subtypes of AMLs and plays a critical oncogenic role in AML by 131 R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 Fig. 2. Landscape of tRNA, rRNA, and mRNA modifications associated with RNA modifications, and their respective RNA-modifying proteins associated with cancer. A. Schematic representation of the tRNA molecule with the specific location and types of predominant RNA modifications and their respective RNA-modifying proteins involved in cancer. B. mRNA. C. rRNA. 132 R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 Fig. 3. Crosstalk between the epitranscriptome and metabolism in cancer initiation and progression. Epigenetic RNA modification pathways in cancer representing the effect of RNA-modifying enzymes and their respective RNA modifications of the expression of genes involved in metabolism and tumorigenesis. Illustration of RNA “writers” such as METTL3, NSUN2, NSUN5, and CTU1, and “erasers” such as FTO, ALKBH5, and ALKBH1. reducing the amount of m6A in ASB2 and RARA mRNA transcripts. proliferation, transformation, invasion, and cancer drug resistance. The Nevertheless, FTO activity as an m6A “eraser” is still a contentious impact of RNA modifications and their enzymes affects almost every issue. Work led by Jaffrey has revealed that FTO preferentially de- aspect of RNA fate and is dependent on cell and tissue-type-specific methylates m6Am (N6,2′-O-dimethyladenosine) present in 5′-caps of context, subcellular localization of the enzymes, responses to several mRNAs, rather than m6A [35]. Moreover, many m6A detection tech- stimuli such as DNA damage, signal transduction pathways, and the nologies inadvertently map m6Am modifications as m6A sites. Thus, availability of energy sources, metabolic substrates, and oxygen. the concept of reversible m6A is still controversial, since the biological Henceforth, recent cancer epitranscriptomics research is focused on role and evidence of its removal are not fully understood, adding a layer the complex cellular context and heterogeneity of RNA molecules and of complexity when trying to associate m6A with cancer progression. cancer, in order to better understand the potential roles of RNA mod- Overall, evidence accumulated to date reveals that the roles of RNA- ifications and their enzymes and explore RNA-modifying enzymes as modifying enzymes differ between different cell subtypes, suggesting potential anticancer drug targets. that the depletion of m6A in different subtypes of AML induces cellular differentiation and apoptosis [31], whereas in other subtypes of AML m6a depletion upregulates oncogenes that promote cell proliferation 4. Interplay between metabolism and epitranscriptomics in and suppress apoptosis [34]. Furthermore, recent discoveries empha- cancer size the importance of the different cellular and molecular contexts in which RNA modifications are regulated. RNA-modifying enzymes The impairment of metabolic programs in cancer has remarkable modulate RNA chemical marks at specific regions of any given RNA effects on epigenetic regulation, contributing to genomic instability. molecule in a context-dependent manner, resulting in different cell fate Metabolites, cosubstrates, and cofactors such as iron, oxygen, ATP, decisions and functional outcomes. First, subcellular localization of acetyl-CoA, SAM, and 2-oxoglutarate have a direct impact on the ac- enzymes modulates accessibility to substrates and substrate preference. tivity of the epigenetic modification enzymes. These epigenetic en- Second, localization and expression of RNA-modifying enzymes can be zymes that transfer methyl, acetyl, and other groups are involved in regulated by their post-translational modifications, contributing to the chemical modifications that influence gene regulation, RNA metabo- spatial regulation of the enzymes [36]. Third, the expression patterns of lism, and chromatin remodeling (Fig. 3). some RNA-modifying enzymes differ between tissues and interact with Cancer cells metabolize glucose, lactate, pyruvate, and glutamine at different protein interaction partners, resulting in the participation of a higher rate than normal cells. In particular, many tumor cells exhibit different signaling pathways. And fourth, the expression of a specific set an altered Krebs or tricarboxylic acid (TCA) cycle, thereby causing an of RNAs could be modulated by environmental signals, hypoxia, nu- accumulation of certain metabolites such as alpha-ketoglutarate (α-KG) trient levels, cytokine signaling, and in response to stimuli, DNA da- that increases the activity of the α-KG-dependent enzymes such as those mage [37], and stress. For more details, these findings have recently of the TET and ALKBH protein families. Thus, the metabolites affect the been extensively reviewed in depth elsewhere [11]. cancer epigenetic landscape. Altogether, RNA-modifying enzymes linked to cancer are crucial The metabolic reprogramming of tumor cells not only enables cells regulators of cell fate decisions and cell differentiation by regulating to adapt to extreme environmental conditions such as stress and hy- RNA metabolism and expression of specific genes required for cell poxia, but also induces metabolic plasticity and heterogeneity by reg- ulating gene expression, cellular differentiation, and the tumor 133 R. Esteve-Puig, et al. Cancer Letters 474 (2020) 127–137 microenvironment. Crosstalk between the complex cancer-associated (Fig. 3). In summary, RNA-modifying enzymes have been associated metabolic reprogramming and cancer epigenetics and epitran- with metabolic and translational reprogramming that ensures enhanced scriptomics has a critical role in tumorigenesis and a deeper under- glycolytic metabolism in cancer. Furthermore, the depletion of the standing of the metabolism and epitranscriptomics in cancer could mcm5s2U “writers” (CTU1 and 2) resensitized drug-resistant melanoma improve clinical outcomes in cancer treatment [12]. cells, indicating their potential as anticancer drug targets. α-KG is an essential endogenous intermediary metabolite in the Taken together, RNA-modifying enzymes are susceptible to changes Krebs cycle that regulates DNA “erasers” and histone modifiers as well in the concentrations of cosubstrates and cofactors such as SAM, 2- as RNA-modifying enzymes such as ALKBH family members (FTO and oxoglutarate, ATP, and acetyl-CoA and are crucial regulators of RNA ALKBH5) (Fig. 3). and cell metabolism, thereby altering metabolic pathways such as R-2-hydroxyglutarate, also known as the oncometabolite R-2HG, is glycolysis, mitochondrial respiratory chain complex activity, and hy- accumulated at high concentrations by the mutant isocitrate dehy- poxia (see examples above). In the past decade, it has been reported drogenases 1/2 (IDH1/2) in tumor cells such as gliomas of grade II-III, that aberrant RNA modifications patterns and RNA-modifying enzymes secondary glioblastoma, and AML. Also, R-2HG is produced by other were involved in cancer initiation and progression, and also in drug enzymes and can cause metabolic alterations in cells lacking IDH mu- resistance. Thus, RNA modifications and RNA-modifying enzymes have tations. R-2HG and α-KG share a similar structure, resulting in R-2HG been demonstrated to affect multiple aspects of RNA metabolism and binding to the same site place as α-KG. Thus, R-2HG acts as a compe- function, resulting in altered cell fate and differentiation in response to titive inhibitor of α-KG, binding to the active sites of specific enzymes cellular signaling and environmental stimuli such as hypoxia, stress, such as α-KG-dependent dioxygenases. As previously discussed, m6A and DNA damage [41]. Regarding the latter, numerous DNA damaging “eraser” FTO, a homolog of the Fe(II) α-KG acid-dependent ALKBH drugs such as the classical DNA-damaging chemotherapy, not only family dioxygenase, is overexpressed in AML. In particular, the FTO damage and modify DNA, but also affect RNA, opening up a promising demethylase plays a role as an oncogene, responsible for the de- new avenue for chemotherapy response prediction [18]. methylation of m6A on ASB2 and RARA mRNA transcripts and ulti- Although the emergent field of the development of epitran- mately promoting cell transformation and leukemogenesis [34]. It has scriptomic drugs is still in its infancy, technological advancement has been documented that inhibition of the FTO demethylase by the on- been essential in significantly accelerating advances in our under- cometabolite R-2HG suppresses leukemia progression by stabilizing standing of epitranscriptomics that have been made in recent years, MYC/CEBPA transcripts [38] (Fig. 3). Different findings indicate, on the indicating that RNA-modifying enzymes may be considered as novel one hand, that R-2HG acts as an oncometabolite in certain subtypes of druggable targets for cancer treatment. Therefore, it is crucial to in- cancer harboring IDH1/2 mutations and, on the other hand, that R-2HG vestigate the molecular mechanisms and the roles of RNA modifications inhibits FTO and promotes antitumor effects. Again, these findings and RNA-modifying enzymes in the appropriate cellular contexts in demonstrate the importance of taking specific contextual factors into order to better leverage advances in cancer treatment. consideration local contexts such as the type of enzyme, the subcellular localization of the enzyme and the cell-type specific context. 5. Discussion To date, a total of 36 RNA methyltransferases have been identified in humans, according to the MODOMICS database. These enzymes 5.1. Challenges in mapping RNA modifications and emerging applications catalyze methylation via a methyl synthase mechanism, using SAM as the source and cofactor to methylate RNA molecules, and importantly, Decoding the complex layer of the epitranscriptome has, up to now, they are a well-known broad group of “writers” involved in human been very challenging. Recent technological advances have, in the past diseases such as cancer [12]. In particular, m6A “writer” METTL3 is the decade, enabled mapping of certain RNA modifications such as m6A best-characterized RNA methyltransferase enzyme associated with and pseudouridine. For instance, the pioneering detection of the m6A cancer, regulating m6A in mRNAs of critical oncogenes and tumor modification was done by antibody-based Next Generation Sequencing, suppressors in a cell-type-specific manner. The majority of human RNA which allows the capture and sequencing of immunoprecipitated RNA methyltransferases (over 27 enzymes) are linked to cancer. Some ex- targets [42]. Some mapping approaches presented several limitations amples are ALKBH8, BCDIN3D, BUD23, CDK5RAP1, DNMT2, ELP3, such as false-positive mapping results, lack of detection of low-abun- Fibrillarin, HENMT1, MePCE, METTL1, 3, 6, 8 and 16, NSUN1-5, dance modifications, possible contaminations of RNA species, low an- RNMT, TRMT1, TRMT10C, 11, 2A, 6, 61A and 61B. METLL16 is an tibody specificity, and Dimroth rearrangement (conversion of m1A to informative example of an important class of SAM-dependent RNA m6A). Currently, the major challenges are the quantification of RNA methyltransferases: METTL16 has been reported to interact with modifications directly at modification sites with higher resolution, cancer-associated lncRNA MALAT1 [39], which transcriptionally reg- precision, and sensitivity as well as improving our understanding of the ulates the expression of MAT2A mRNA, which encodes the SAM syn- molecular mechanisms and functional roles of RNA modifications and thetase (Fig. 3). Under SAM-limiting conditions, METTL16 promotes RNA-modifying enzymes. However, technology is rapidly progressing MAT2A splicing, indicating that cells control SAM homeostasis by and novel methodologies for more precise and sensitive detection, regulating SAM synthetase gene expression. imaging and quantification of RNA modifications are emerging, such as Hypoxia in cancer leads to the inhibition of biosynthetic reactions deamination adjacent to RNA modification targets (DART-seq), phage that require oxygen, switching from oxidative phosphorylation to display antibody technology and direct sequencing through nanopores anaerobic glycolysis, resulting in ER stress induction and apoptosis in [12] (third-generation sequencing technologies), and fluorescent nu- tumor cells. For example, it has been reported that the U34 enzymes cleobases [43] will enable the global detection and determination of that catalyze modification of wobble uridine 34 tRNA promote glyco- stoichiometries of RNA modifications, even for RNA modifications at lysis, survival, and resistance to melanoma therapy through the main- very low stoichiometries, as well as the study of concomitant and tenance of a high amount of HIF1-α protein [40]. In particular, U34 combinatorial RNA modification profiles. enzymes CTU1 and CTU2, play a central role in the 2-thiolation of mcm5S2U modification on tRNA and were found to be upregulated in 5.2. Clinical oncology impact BRAF mutant melanoma, conferring survival and drug resistance. 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