- Open Access
Novel insights on m6A RNA methylation in tumorigenesis: a double-edged sword
Molecular Cancer volume 17, Article number: 101 (2018)
N6-methyladenosine (m6A), the most prevalent modification of mammalian RNA, has received increasing attention. Although m6A has been shown to be associated with biological activities, such as spermatogenesis modulation, cell spermatogenesis and pluripotency, Drosophila sex determination, and the control of T cell homeostasis and response to heat shock, little is known about its roles in cancer biology and cancer stem cells. Recent articles have noted that some genes have abnormal m6A expression after tumorigenesis, including genes ABS2, RARA, MYB, MYC, ADAM19 and FOX1. Abnormal changes in the m6A levels of these genes are closely related to tumour occurrence and development. In this review, we summarized the ‘dual edge weapon’ role of RNA methylation in the tumorigenesis. We discussed RNA methylation could lead to not only tumour progression but also tumour suppression. Moreover, we clarified that the abnormal changes in the m6A enrichment of specific loci contribute to tumour occurrence and development, thereby representing a novel anti-cancer strategy by restoration to balanced RNA methylation in tumour cells.
Approximately 100 different post-transcriptional chemical modifications are present in RNA among all living organisms . N6-methyladenosine (m6A), one such modification, was identified in the 1970s as the most abundant internal chemical modification in eukaryotic mRNA . Approximately 0.1–0.4% of adenosine nucleotides in isolated mammalian RNA are chemically modified . Extensive m6A modifications are present in the RNA of plants and vertebrates, and these modifications also occur in the RNA of single-celled organisms, such as bacteria and yeast [2, 4,5,6,7]. m6A-based modifications occur at a consensus motif, RRm6ACH([G/A/U][G > A]m6 AC[U > A > C])  (Fig. 1). Furthermore, m6A is mainly concentrated on stop codons, in 3′ untranslated regions (3’UTRs), and within internal long exons, based on detection with m6A-specific antibodies and high-throughput sequencing . A multicomponent methyltransferase complex catalysing m6A formation was first reported in 1994 . Subsequently, methyltransferase-like 3 (METTL3), which functions as an S-adenosyl methionine-binding protein, was the first protein found to possess methyltransferase capacity . Later, other m6A methyltransferase components were gradually discovered in mammals, including Wilms tumour 1-associated protein (WTAP), methyltransferase-like 14 (METTL14), RNA binding motif protein 15 (RBM15), KIAA1429 and zinc finger CCCH-type containing 13 (ZC3H13) (‘writers’) [12,13,14,15]. METTL3 and METTL14 form a stable complex in mammalian cells that accurately localizes at methylation sites by associating with WTAP . The catalytic methylation activity of METTL14 is approximately 10 times that of METTL3, but WTAP has no catalytic methylation activity . Recently, methyltransferase-like protein 16 (METTL16) was confirmed to be a m6A methyltransferase that methylates U6 spliceosomal RNA and interacts with the 3′-terminal RNA triple helix of metastasis-associated lung adenocarcinoma transcript 1(MALAT1) . In 2011, the first demethylase fat mass and obesity-associated protein (FTO) was identified, demonstrating that m6A modifications on mRNA are reversible and dynamic . FTO and alkB homologue 5 (ALKBH5) function as two kinds of demethylases (‘erasers’) and may target distinct sets of target mRNAs [18, 19]. Members of the YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1 and YTHDC2) have a conserved m6A-binding pocket and directly read m6A-mediated physiological effects [9, 20,21,22,23,24,25]. Heterogeneous nuclear ribonucleoprotein (HNRNP) proteins HNRNPA2B1 and HNRNPC selectively bind m6A-containing mRNAs to respond to physiological effects [26, 27]. These proteins influence mRNA processing by impacting functions such as mRNA splicing, export, and translation initiation [24, 26, 28]. Recently, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) were found to recognize m6A RNA modifications, functioning as a distinct family of m6A readers . In addition, fragile X mental retardation 1 (FMR1) and leucine rich pentatricopeptide repeat containing (LRPPRC) read m6A modifications on target loci and influence RNA behaviour  (Fig. 1).
N6-methyladenosine represents one of the most common RNA modifications in eukaryotes, regulating RNA behaviours such as splicing or the ability to code diverse proteins [9, 20,21,22,23,24,25]. Recently, aberrant m6A modification in the large internal exon of a tumour suppressor was shown to give rise to premature polyadenylation, leading to membrane associated guanylate kinase (MAGI3) inactivation . In addition, m6A regulates other forms of RNA modification. There is a significant negative correlation between two distinct and abundant RNA modifications, m6A and adenosine-to-inosine (A-to-I), suggesting a previously underappreciated interplay between them . N6-methyladenosine also affects the function of Long non-coding RNA (LincRNA). LincRNA 1281 is required for proper differentiation of mouse embryonic stem cells, and this critical function relies on sufficient m6A modification . m6A may also play a functional role by regulating histones and DNA. The homeostatic regulation of S-adenosylmethionine (SAM) synthesis in mammalian cells involves dynamic m6A modifications on the 3’UTR of methionine adenosyltransferase 2A (MAT2A) . In this review, we will briefly introduce physiological activities related to m6A modification. Then, we will describe in detail the ability of m6A modifications, functioning as a double-edged sword, to play a regulatory role in tumorigenesis and development.
Physiologic functions of m6A modifications
The dynamic reversibility of m6A methylation suggests that it plays an important role in physiological processes. Studies have revealed that m6A modifications on mRNAs or non-coding RNAs play important roles in spermatogenesis, T cell homeostasis, Drosophila sex determination, heat shock responses, pluripotency and reprogramming, as well as other processes [27, 35,36,37,38,39] (Table 1).
m6A modulates spermatogenesis
The process by which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa is called spermatogenesis . m6A is reportedly present on the key regulatory factors of SSCs/progenitor cells, such as Plzf, Id4, Dnmt3b, and Sohlh2, which control the timing of transcript translation to coordinate normal protein generation, and this modification is essential for mammalian spermatogenesis . m6A deletion resulted in the dysregulation of proliferation and differentiation factors of SSC/progenitor cells and SSC depletion .
m6A influences T cell homeostasis
Peripheral T cells are subject to complex and rigorous regulation, and the interleukin 7(IL-7)/signal transducer and activator of transcription 5(STAT5) signal axis is highly significant for maintaining naive T cell homeostasis and survival . Decreased levels of m6A modification on the mRNAs of suppressor of cytokine signalling (SOCS) family genes have been reported to slow mRNA decay and increase protein expression levels (SOCS1, SOCS3 and CISH) in naive T cells . Overexpression of SOCS1, SOCS3 and CISH leads to the inhibition of the downstream signal IL-7/STAT5, preventing naive T cell proliferation and differentiation while maintaining T cell survival . Thus, m6A modifications are known to play an important role in T cell homeostasis.
m6A is involved in Drosophila sex determination
Mammalian m6A enzyme complexes include including WTAP, METTL14, RBM15, KIAA1429 and ZC3H13 [12,13,14,15]. The corresponding m6A methylation enzyme analogues in Drosophila include inducer of meiosis 4 (Ime4), karyogamy protein 4 (KAR4), female-lethal(2)d(Fl(2)d) and virilizer(Vir) [11, 12, 41,42,43]. The m6A reader protein YT521-B has been reported to read m6A modifications on Sxl to promote Sxl alternative splicing, which determines female physiognomy . The ability of YT521-B to read m6A explains the importance of this modification in Drosophila sex determination through the selective splicing of Sxl .
High levels of m6A during the heat shock response
The heat shock response is a complex cellular reaction that causes significant changes in protein translation, folding and degradation, thereby mitigating toxic reactions caused by protein misfolding . m6A and the heat shock response are linked because m6A is the most abundant mRNA post-transcriptional modification. A new report has revealed that m6A is preferentially deposited on the 5’UTR of new stress-inducible transcripts, such as Hsp105 (HSPH1), under heat shock stress, and that increased levels of m6A modification at the 5’UTR can enhance cap-independent translation initiation . Thus, the mechanistic connection between 5’UTR methylation and cap-independent translation reveals links between the heat shock response and m6A .
m6A influences somatic cell reprogramming and maintains the pluripotency of embryonic stem cells (ESCs)
Epigenetic and epitranscriptomic networks play important roles in somatic cell reprogramming and the maintenance of ESC pluripotency . A new study has revealed that zinc finger protein 217 (ZFP217) activates the transcription of key pluripotency genes and modulates m6A deposition on their transcripts . ZFP217 depletion globally enhances m6A modification on Nanog, Sox2, Klf4, and c-Myc mRNAs to accelerate their degradation, thus damaging ESC self-renewal and somatic cell reprogramming . This finding represents strong evidence of the close relationships between m6A and somatic cell reprogramming and the maintenance of ESC pluripotency.
Aberrant m6 A modification contributes to diversified tumours
Given the important role of RNA m6A modification in regulating gene expression and various biological processes , it is reasonable to speculate that aberrant m6A modification plays an important role in human carcinogenesis. However, knowledge of the mechanistic link between m6A and human carcinogenesis is rather limited. While investigations addressing this issue are still at an early stage, efforts are underway to explore the biological impacts of m6A modifications in cancer. We will summarize recent reports describing our understanding of the biological functions and underlying molecular mechanisms of m6A regulatory proteins in various types of cancer and explore new options for cancer treatment (Fig. 2 and Table 2).
Connection between m6A and acute myeloid leukaemia (AML)
AML is one of the most common haematopoietic malignancies and is associated with a high mortality and distinct genetic and molecular abnormalities that lead to unsatisfactory therapeutic effects [45, 46]. Only a small proportion of patients survive for more than 5 years with standard chemotherapies [45, 46]. Therefore, it is urgent and necessary to explore new treatments for AML based on a deep understanding of the mechanisms of AML occurrence and development.
FTO, an obesity risk-associated gene and the first m6A eraser to be identified, has been reported to play an important oncogenic role in haematopoietic cell transformation and AML [17, 47]. FTO levels in certain subtypes of AML (e.g., t(11q23)/MLL-rearranged, t(15;17), FLT3-ITD, and/or NPM1-mutated) are abnormally elevated, which leads to the downregulation of m6A levels on the UTRs of ASB2 and RARA . These low levels of m6A reduce the mRNA and protein levels of these two genes . FTO is not the only demethylase with a link with AML; METTL14 also plays an important oncogenic role in this disease by regulating its mRNA targets (e.g., MYB, MYC) through m6A modifications, which in turn leads to enhanced MYB and MYC expression and ultimately blocks myeloid differentiation . Additionally, a new report has shown that FTO promotes the stability of MYC mRNA by inhibiting YTHDF2-mediated RNA decay, which is attributed to decreased m6A abundance on the 5′-terminal and internal exons of MYC mRNA, indicating that m6A modifications on different regions of the same mRNA transcript (e.g., MYC) lead to distinct fates [48, 49].
Furthermore, it has been reported that the presence of increased METTL3 levels in AML leads to higher m6A methylation levels of BCL2 and PTEN and promotes the translation of BCL2 and PTEN mRNA, which ultimately leads to tumour formation . Recently, another study revealed that METTL3 binds to the promoter region of SP1 with the aid of transcription factor CEBPZ, which enhances m6A modification of SP1, strengthens SP1 gene expression, and ultimately leads to myeloid leukaemia . In general, changes in m6A modification levels on ASB2, RARA, MYC, MYB, BCL2, SP1and PTEN eventually lead to the occurrence of AML [47,48,49,50].
Aberrant m6A in hepatocellular carcinoma (HCC)
HCC is a major type of primary liver cancer, accounting for the 5th highest incidence of malignant tumours worldwide and causing more than 700,000 annual deaths . The prevalence of hepatitis B and C viruses in Asia is the main cause of the high incidence of liver cancer in Asia . Effective interventions are lacking, resulting in high HCC mortality due to metastasis and recurrence; thus, a deeper understanding of the molecular mechanism underlying the occurrence and development of HCC is required. Growing evidence suggests that the occurrence of liver cancer is a multistep process involving complex interactions between genetics, epigenetics and transcriptional changes . Previous studies have shown that DNA hypermethylation occurs on CpG islands of the promoter regions of tumour suppressor genes, such as DLC1, TFPI-2, CDKN2A, and PTEN, ultimately affecting tumorigenesis and development [54,55,56]. It was reported that high levels of the histone methyltransferases EZH2, SUV39H1, SETDB1 and G9a promote the development and metastasis of HCC via epigenetic silencing of critical tumour suppressor genes [57,58,59]. In general, abnormal epigenetic modifications may be important factors in the development of liver cancer.
Many articles note that the development of liver cancer is associated with abnormal m6A modifications [60, 61]. The high expression of METTL3 in human HCC reportedly leads to increased m6A modification levels on the tumour suppressor SOCS2 . Excessive m6A chemical modification of SOCS2 is read by YTHDF2, which accelerates the degradation of SOCS2 and eventually leads to the occurrence of HCC . Another report has indicated that decreased METTL14 expression reduces m6A modification levels and the expression of microRNA126 (miR126) . Low m6A modification levels on miR126 are recognized by DGCR8 and may ultimately promote liver carcinogenesis . These articles strongly suggest that abnormal m6A modification plays an important role in the occurrence and development of HCC.
The foundation role of m6A in glioblastoma stem cells (GSCs)
Glioblastomas are primary brain tumours with a high degree of malignancy . The median survival time after diagnosis is usually less than 15 months, even if diagnosis is combined with surgical resection, radiotherapy and chemotherapy [62, 63]. GSCs are a group of tumour stem cells with the ability to promote tumour growth and invasion, showing strong resistance to radiotherapy and chemotherapy; these characteristics are the main reasons for the poor prognosis of glioblastoma [64,65,66,67]. Therefore, the issue of stem cell resistance should be explored and addressed to improve therapeutic approaches to glioblastoma [66, 68]. RNA epigenetics has become a rapidly developing field in biology and may be valuable for informing glioblastoma treatment.
A study showed that low levels of METTL3 or METTL14, key components of the RNA methyltransferase complex, lead to decreased m6A modification levels on ADAM19 and the enhanced expression of ADAM19 in GSCs, ultimately causing glioblastoma . Low m6A modification levels on ADAM19 and high mRNA expression levels of ADAM19 may represent a promising target for anti-glioblastoma therapy . Another study revealed that aberrant m6A modifications caused by high levels of ALKBH5, an m6A demethylase, are an obvious physiological abnormality of GSCs . Decreased m6A modification levels of FOXM1 result in enhanced FOXM1 expression levels, which ultimately cause glioblastoma . Aberrant m6A modifications caused by different mechanisms in GSCs strongly suggest that this modification is related to the occurrence and development of glioblastoma.
Abnormal m6A modification in breast cancer
Among all malignant tumours in women, breast cancer has the highest incidence and leads to the highest number of deaths [71, 72]. Although the therapeutic outcomes of early-stage breast cancer are relatively good, treatments for metastasis are not effective . Given the high recurrence and mortality rate, the molecular mechanisms that regulate breast cancer phenotypes need to be carefully delineated and studied to design more effective therapies.
In breast cancer stem cells (BCSCs), ZNF217 has been reported to interact with METTL3 and inhibit the m6A methylation of KLF4 and NANOG, which ultimately leads to high expression of KLF4 and NANOG, thus promoting tumorigenesis . Another report indicated that high m6A modification levels on hepatitis B X-interacting protein (HBXIP) and the overexpression of HBXIP caused by high METTL3 levels accelerate the proliferation of BCSCs . In addition, a study revealed that high levels of m6A modification on MAGI3 lead to premature polyadenylation, switching its functional role from a tumour suppressor gene to a dominant-negative oncogene and ultimately promoting tumorigenesis of breast cancer . The aberrant m6A modifications caused by different mechanisms in breast cancer prove that this modification is related to the occurrence and development of breast cancer.
Aberrant m6A modification in cervical cancer
Cervical cancer is one of the most common and destructive gynaecological malignancies . Chemoradiotherapy is the major therapy used to treat cervical squamous cell carcinoma . However, chemoradiotherapy resistance is the major cause of treatment failure. Therefore, it is necessary to further understand the molecular mechanisms underlying chemoradiotherapy resistance and explore novel therapeutic treatments for cervical squamous cell carcinoma (CSCC) .
In CSCC, the expression of FTO is significantly higher than that in normal tissues, resulting in lower levels of m6A modification in β-catenin, which causes decreased expression of β-catenin and chemoradiotherapy resistance. The discovery of this mechanism suggests that MA2, a novel small molecular inhibitor of FTO, may increase the chemoradiotherapy sensitivity of CSCC .
METTL3 promotes the translation of oncogenes in human lung cancer
Lung cancer is one of the most common malignant tumours in humans, causing many deaths every year [80, 81]. The 5-year survival rate of lung cancer patients is still very low despite continuous improvement and progress in the diagnosis and treatment of lung cancer [82, 83]. Non-small-cell lung carcinoma (NSCLC) accounts for 85% of all pathological types of lung cancer [82, 83]. Our attention should be focused on the abnormal molecular biological characteristics of NSCLC to find an effective treatment.
Many articles have reported that abnormal m6A modifications ultimately affect tumour development. However, one report indicated that in lung cancer, METTL3 associates with translation machinery and enhances the translation of target mRNA (RGFR and TAZ) independent of its methyltransferase activity . Another report also indicated that miR-33a prohibits NSCLC cell proliferation by targeting METTL3, which suggests that miR-33a may be a potential molecule for therapy . Moreover, post-translational modification of METTL3 has been revealed. For example, METTL3 is modified by SUMO1, and SUMOylation of METTL3 decreases m6A levels on mRNAs, which ultimately promotes the development of NSCLC .
m6A leads to the acceleration of tumour formation
In AML, upregulated m6A modification on MYB, MYC, BCL2, PTEN and SP1 results in enhancement of the binding capability and translational efficiency of onco-RNA and ribosomes, leading to tumorigenesis [47,48,49,50]. Moreover, in hepatocellular carcinoma, the excessive m6A modification of the SOCS2 tumour suppressor gene reduces mRNA stability and accelerates its degradation, which causes tumour progression . In addition, in breast cancer, upregulated m6A modification of HBXIP and MAGI3 results in tumour formation . It is worth noting that excessive modification of MAGI3 leads to premature polyadenylation, switching its functional role from that of a tumour suppressor gene to a dominant-negative oncogene, ultimately promoting tumorigenesis . In summary, RNA methylation triggers certain alterations to tumour-specific mRNA behaviour and results in changes in onco-protein expression and biologic activity, thereby accelerating the tumour progression.
m6A contributes to the inhibition of tumour development
In contrast, the aberrant decreased m6A modification levels on target loci can also disrupt normal RNA functions, which in turn restores normal m6A levels on these targets and ideally suppresses tumour formation. The FTO-mediated downregulation of m6A modification levels on ASB2 and RARA leads to the downregulation of these anti-oncogenes via RNA and protein degradation, leading to the promotion of tumorigenesis . In hepatocellular carcinoma, the decreased m6A modification levels on microRNA126 influence its function as a ceRNA and disrupt its regulation of binding capability, thereby triggering the acceleration of tumour development .
Similarly, in GSCs, a long non-coding RNA FOXM1-AS directly binds to FOXM1 mRNA, enhancing the interaction between ALKBH5 and FOXM1 nascent transcripts and giving rise to reduced m6A modification levels and the overexpression of this oncogene . Additionally, decreased m6A modification levels enhance the RNA stability of KLF4 and NANOG and ultimately contribute to tumour formation . In summary, it has been revealed that decreased RNA methylation may participate in tumorigenesis. Therefore, a novel therapeutic strategy may involve tumour suppression via enhanced m6A modification to balance the transcription of these genes.
In summary, an increasing number of studies has shown that aberrant m6A modification is closely related to tumorigenesis, including AML, HCC, GSCs, breast cancer, cervical cancer and lung cancer [50, 60, 70, 75, 79]. Moreover, numerous genes modified by m6A have been revealed to play regulatory roles in tumour formation, such as BCL2, PTEN, SOCS2, FOXM1 and HBXIP [50, 60, 70, 75, 79]. In conclusion, m6A modification is a double-edged sword, over-modification of a target gene by m6A could result in altered RNA splicing and translational capability, leading to the acceleration of cancer formation, whereas the lack of m6A modification at other loci may also contribute to tumorigenesis.
Abnormal levels of m6A methylation may give rise to tumour progression. However, we should not ignore the notion that RNA methylation enzymes influence tumorigenesis in an m6A-independent manner. For example, in lung cancer, METTL3 directly associates with translation machinery and enhances the translation of target mRNA (RGFR and TAZ) independent of its methyltransferase activity .
This review updates our knowledge of the aberrant m6A methylation of diverse target loci and discusses its impact on tumour formation. Aberrant levels of m6A modification, such as increased or decreased levels, may alter RNA splicing, RNA-coding capability or onco- or tumour suppressor genes. To discover novel tumour therapies based on the evaluation of m6A modifications, it should be noted that m6A functions as a dual-edged weapon; thus, restoring ideal levels of m6A (rather than simply over-supplementing or over-silencing) holds great significance.
3′ untranslated regions
- ADAM19 :
A disintegrin and metallopeptidase domain 19
AlkB homologue 5
Acute myeloid leukaemia
- ASB2 :
Ankyrin repeat and SOCS box containing 2
- BCL2 :
B cell leukaemia 2
Breast cancer stem cells
- CDKN2A :
Cyclin dependent kinase inhibitor 2A
- CISH :
Cytokine inducible SH2 containing protein
Cervical squamous cell carcinoma
- Dnmt3b :
DNA methyltransferase 3B
Embryonic stem cells
- EZH2 :
Enhancer of zeste 2 polycomb repressive complex 2 subunit
Fragile X mental retardation 1
- FOXM1 :
Forkhead box M1
Fat mass and obesity-associated protein
Glioblastoma stem cells
- HBXIP :
Hepatitis B X-interacting protein
Heterogeneous nuclear ribonucleoprotein
- Id4 :
Inhibitor of DNA binding 4
Insulin-like growth factor 2 mRNA-binding proteins
- IL-7 :
Inducer of meiosis 4
Karyogamy protein 4
- Klf4 :
Kruppel like factor 4
- KLF4 :
Kruppel like factor 4
Leucine rich pentatricopeptide repeat containing
- MAGI3 :
Membrane associated guanylate kinase
- MAGI3 :
Membrane associated guanylate kinase, WW and PDZ
- MALAT1 :
Metastasis-associated lung adenocarcinoma transcript 1
- MAT2A :
Methionine adenosyl transferase 2A
Methyltransferase-like protein 16
- MYB :
- MYC :
- NANOG :
Non-small-cell lung carcinoma
- Plzf :
Promyelocytic leukaemia zinc finger
- PTEN :
Phosphatase and tensin homolog
- RARA :
Retinoic acid receptor alpha
RNA binding motif protein 15
- SETDB :
SET domain bifurcated 1
- SOCS2 :
Suppressor of cytokine signaling 2
- Sohlh2 :
Spermatogenesis and oogenesis specific basic helix-loop-helix 2
- Sox2 :
Sex determining region Y box 2
Spermatogonial stem cells
- STAT5 :
Activator of transcription 5
Small ubiquitin-like modifier 1
- SUV39H1 :
Suppressor of variegation 3–9 homolog 1
- Sxl :
- TFPI-2 :
Tissue factor pathway inhibitor 2
Wilms tumour 1-associated protein
Zinc finger CCCH-type containing 13
- ZFP217 :
Zinc finger protein 217
- ZNF217 :
Zinc finger protein 217
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This work was supported by the National Natural Science Foundation of China grant (81602366, 81402258, 81570884), the Scientific Research Program of National Health and Family Planning Commission of China (201402014), the ShuGuang Project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation (14SG18), and the Science and Technology Commission of Shanghai (17DZ2260100).
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Wang, S., Chai, P., Jia, R. et al. Novel insights on m6A RNA methylation in tumorigenesis: a double-edged sword. Mol Cancer 17, 101 (2018) doi:10.1186/s12943-018-0847-4
- RNA methylation