Research progress concerning m6A methylation and cancer (Review)
- Authors:
- Published online on: September 10, 2021 https://doi.org/10.3892/ol.2021.13036
- Article Number: 775
-
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Cancer is a gene-related disease with heredity and can be caused by various physical, chemical or biological factors (1). It is usually characterized by abnormal differentiation and proliferation of cells, which differ from normal cell proliferation and apoptosis (2). In addition, tumor cells have invasive and metastasis abilities, and promote angiogenesis. N6-methyladenosine (m6A) methylation is an epigenetic modification of RNA, first discovered in the mRNA of eukaryotes in the 1970s (3). However, due to the limitation of technology, scientists hypothesized that the m6A methylation site only existed in mRNA. In recent years, m6A methylation has been found in different types of RNA, such as long non-coding RNA (lncRNA) (4), microRNA (5) and mRNA (6). With the rapid development of high-throughput sequencing technology, a variety of bioinformatics platforms, for predicting m6A methylation sites, have been developed, which increased the investigation of m6A methylation (7). In the process of carcinogenesis, m6A methylation has been associated with the occurrence and development of cancer by regulating the expression level of oncogenes and cancer suppressor genes. For example, in leukemia, METTL-14 causes the occurrence and development of leukemia via m6A RNA modification of MYB/myc (8). In liver cancer, METTL-3 promotes cancer progression through YTHDF2 dependent posttranscriptional silencing of SOCS2 (9). Similar to DNA methylation, m6A methylation is regulated by methyltransferase and demethylase, which modulates post-transcriptional modifications without alternating the gene sequence (10). However, its regulatory mechanism is more complicated than DNA methylation. The present review explains the m6A-related enzymes, research methods and research progress of m6A methylation and cancer, and to describe the association between m6A methylation and tumor occurrence and development. An improved understanding of m6A methylation could assist with identifying potential biomarkers and targets for molecular diagnosis and targeted therapy of cancer.
Composition and function of m6A modified enzyme
m6A is a dynamic and reversible modification process, which mainly involves three types of catalytic enzymes: Methyltransferase, demethylase and methylated reading protein (Table I). Methyltransferase, also known as mRNA ‘writer’, methylates adenosine in mRNA (11). METTL-14 and METTL-3 can form a methyltransferase complex by binding to the regulatory protein, WT1 associated protein (WTAP) and subsequently promote methylation. m6A modified mRNA specifically binds to methylated reading protein, termed as ‘reader’, and results in various effects on gene expression (12). Demethylase (mRNA erasers) can remove the methyl group on adenosine bases for m6A demethylation. The mRNA writers and erasers make m6A modification a dynamic and reversible process. Previous studies hypothesized that m6A modification could change the secondary structure of RNA, promote the combination of RNA binding protein with RNA segments, interfere with RNA modification and subsequently regulate gene expression (13,14). However, the underlying mechanism remains unclear.
mRNA writers
m6A methylation is catalyzed by mRNA writers, including METTL-3, METTL-14, WTAP, VIRMA and RBM15. The core components of the m6A methyltransferase complex (METTL-3, METTL-14, WTAP and VIR) are highly conserved in most eukaryotes (15). The study of the m6A site on human small nuclear (sn) RNA U6 showed that human cells express at least one activated m6A methyltransferase, apart from METTL-14 and METTL-3. However, these enzymes have not been identified due to the limitation in technology.
METTL-3
METTL-3, also known as MT-A70, is the earliest reported m6A methylase. Barbieri et al (16) reported that the upregulation of METTL-3 expression significantly promoted the m6A methylation of mRNA transcribed by the oncogene SP1, resulting in an increased expression of the SP1 protein, which was associated with the differentiation of hematopoietic stem cells into acute myeloid leukemia (AML) cells. In addition, Vu et al (17). confirmed that downregulation of METTL-3 gene expression increased the phosphorylation of AKT and promoted the differentiation of hematopoietic stem cells into AML cells. The two studies provide novel directions for the diagnosis and treatment of AML.
In addition, some studies have shown that under hypoxia, the transcription factor zinc-finger protein 217 (ZNF217) inhibited the m6A modification of KLF4 and NANOG by binding to METTL-3, leading to elevated expression of KLF4 and NANOG, and the promotion of breast cancer (18). Cai et al (19) have found that high expression of METTL-3 in breast cancer cells induced m6A modification on HBXIP mRNA. HBXIP promoted the m6A modification of METTL-3 by reducing the expression level of tumor suppressor gene LET-7G, which forms a positive feedback pathway with HBXIP/LET-7G/METTL-3/HBXIP and promoted the malignant biological behaviors of breast cancer. These studies provide new approaches for the diagnosis and treatment of breast cancer.
Furthermore, Chen et al (9) found that overexpressed METTL-3 in primary hepatocellular carcinoma (HCC) could change the m6A modification of the tumor suppressor gene, SOCS2, leading to degradation of SOCS2 mRNA and promotion of cancer cell proliferation and migration. This study showed that hypermethylation was associated with the progression of HCC. Taketo et al (20) found that, in pancreatic cancer cell lines with low expression of METTL-3, the cancer cells were more sensitive to gemcitabine and other anticancer drugs [Everolimus (21) or Elemene (22)] and external radiation. In addition, METTL-3 was associated with cell cycle regulation, mitogen-activated protein kinase cascade and RNA splicing, suggesting that METTL-3 may be one of the potential targets to improve the therapeutic efficacy in patients with pancreatic cancer.
However, in renal cell carcinoma (RCC), METTL-3 exhibited tumor-suppressing activity (23). In vivo experiments confirmed that lower expression of METTL-3 was significantly associated with tumor histological grade and tumor size. In addition, patients with RCC and overexpression of METTL-3 had a higher overall survival rate and good prognosis. Downregulation of the METTL-3 gene expression in a RCC cell line could promote cell epithelial-mesenchymal transition (EMT), proliferation, invasion and metastasis. It was suggested that METTL-3 could be used as a new marker for the treatment of RCC, however, further studies are required to investigate the role of METTL-3 and related factors in carcinogenesis to further understand the biological mechanism of the occurrence and development of RCC.
The aforementioned studies have investigated the different activities of METTL-3 in various types of cancer, indicating that m6A methyltransferase, METTL-3 could be a potential target for developing novel therapeutic strategies, and investigating the mechanism of the occurrence and development of cancer.
METTL-14
METTL-14 is a homologous heterodimer of METTL-3 in the MT-A70 methyltransferase family (24). It has been reported that knockout of the METTL-14 gene in HeLa cells led to a decrease in m6A methylation level, suggesting that METTL-14 was an important part of the m6A methyltransferase complex (25). Since METTL-3 is a subunit with catalytic activity, METTL-14 is responsible for identifying substrates. The two proteins are combined to form a stable methyltransferase complex with a ratio of 1:1 In vivo, which allows the catalyzation of m6A modification in target RNA (26). Weng et al (8) found that the knockout of METTL-14 in AML cell lines could effectively inhibit the proliferation of the AML cells. METTL-14 was negatively regulated by SP1 at the protein level and induced cancer promotion by regulating target genes via m6A modification. This study firstly revealed the role of the SP1-METTL-14-MYB/MYC signal axis in the progression, maintenance, and self-renewal of leukemia, providing new ideas for the diagnosis and treatment of AML. In addition, Ma et al (27) proved that the decrease in expression of METTL-14 in HCC tissue was an independent factor in predicting cancer recurrence. The reduction of METTL-14 led to a decreased level of m6A methylation, which inhibited cell proliferation and promoted apoptosis of HCC cells. In a HCC cell line, METTL-14 mediated the decreased expression of miR-126, leading to the invasion and metastasis of HCC. Furthermore, Ma et al also found that the expression level of METTL-14 and demethylase WTAP in HCC was decreased, indicating that m6A modification has a complicated feedback regulation mechanism. Therefore, the investigation into the interaction between METTL-14 and micro (mi) RNA could provide novel targets for the treatment of HCC.
METTL-16
METTL-16 is a newly discovered m6A methyltransferase (28). The downregulated expression of METTL-16 led to a decrease in the level of m6A methylation in cells. Warda et al (29) found that METTL-16 could bind to snRNA U6, long non-coding (lnc) RNA and pre-mRNA via cDNA cross-linking analysis, which deepened the understanding of the interaction between m6A and other RNA.
S-adenosylmethionine (SAM) is an important methyl donor of DNA methylation and acts as a key regulator controlling gene expression (30). It has previously been reported that SAM played an important role in RNA methylation (31). The study suggested that METTL-16 maintained the stability of intracellular SAM by regulating the alternative splicing of MAT2A. The absence of SAM increased the residence time of METTL-16 in the hairpin of MAT2A 3′ untranslated region (UTR) and promoted the alternative splicing of MAT2A, subsequently regulating the homeostasis of intracellular SAM content (32). The association between RNA modification and alternative splicing was established by this mechanism. However, the association between METTL-16 and the occurrence and development of cancer remains unclear. Therefore, further studies are required to investigate the role of METTL-16 in cancer development.
WTAP
WTAP is an essential component in m6A methylation modification. Ping et al (33) proved that WTAP assisted with the accurate location of the METTL-3-METTL-14 heterodimer and promoted m6A methylation. In addition, either knockdown or overexpression of METTL-3 led to an elevation of WTAP expression, indicating that METTL-3 plays an important role in the regulation of WTAP function (34). However, the upregulation of WTAP could not promote cancer cell proliferation in the absence of METTL-3. Therefore, the carcinogenic effect of WTAP is associated with the m6A methyltransferase complex. The association between WTAP and the occurrence and development of cancer is unclear. Xi et al (35) found that WTAP was highly expressed in glioma tissue and was associated with pathological grade and poor postoperative survival rate. Li et al (36) confirmed that the expression level of WTAP was significantly increased in both the cytoplasm and nucleus of pancreatic ductal adenocarcinoma (PDAC), whereas the high expression level in the nucleus was significantly associated with sex and tumor stage and was considered to be an independent prognostic factor of PDAC. Tang et al (37) reported that the high expression level of WTAP in patients with RCC was associated with poor overall survival rate and prognosis. The study also found that WTAP may promote the proliferation of RCC cells by regulating the stability of CDK2 mRNA, leading to the occurrence and development of cancer. Therefore, WTAP may become a new target for the diagnosis and treatment of RCC.
mRNA erasers
α-ketoglutarate-dependent dioxygenase FTO protein (FTO) encoded by the obesity gene, FTO was the first demethylase found in mammals, which proved that m6A modification was dynamically reversible (38). Similarly, AlkB homologous protein 5 (ALKBH5) in mammals could also catalyze the restoration of m6A methylation (39). Currently, it is not clear whether demethylases exist in lower-grade eukaryotes. Some studies have found that when the first nucleotide adjacent to the cap in the nucleotide sequence is adenosine, FTO cannot induce demethylation, but the specific mechanism is unclear.
FTO
The FTO gene is located on chromosome 16 (16q12.2) and is widely expressed in all stages of human growth (40). Its main functions are to regulate the rate of fat consumption, promote the overall metabolic rate, and ensure the energy balance of the body (41). Jia et al (42) first confirmed that the FTO protein was a crucial demethylase in both DNA and RNA modification, especially in m6A demethylation. This report ushered in the era of m6A research. Selberg et al (26) confirmed that the level of m6A in mRNA was increased in FTO knockout leukemia cells or gastric cancer cells and vice versa. However, the expression of m6A methylase METTL-3 was not affected. Based on these results, researchers preliminarily proved that the methylation process of m6A was reversibly and dynamically regulated. Previous studies have shown that the expression of the FTO gene was associated with breast cancer (41), thyroid cancer (43), endometrial cancer (44), gastric cancer (45), and other types of cancer (46,47). Li et al (48) found that FTO increased leukemia oncogene-mediated cell transformation and leukemogenesis by reducing the m6A modification of ASB2 and RARA genes, which led to the inhibition of AML cell differentiation induced by all-trans retinoic acid. In another study, Zhou et al (49) found that the expression of the FTO gene was significantly increased in patients with cervical squamous cell carcinoma (CSCC), and the increased expression of FTO and β-catenin indicated a poor prognosis. Therefore, the expression level of FTO and β-catenin could predict the prognosis of CSCC. In short, few studies have focused on the mechanism of FTO-induced m6A modification in the carcinogenesis and development of cancer. More studies are required to clarify the relevant molecular biological mechanisms involved in FTO-induced m6A modification. However, it remains controversial whether the activity of methylase and demethylase is limited to catalyzing m6A modification on RNA.
ALKBH5
ALKBH5 belongs to the AIkB family, but unlike other family members, ALKBH5 only has demethylation ability on single-stranded RNA/DNA (50). With the participation of hypoxia-inducible factors (HIF), ALKBH5 can induce the transformation of breast cancer cells into tumor stem cells by reducing the m6A methylation of NANONG, which improves the stability of NANONG mRNA and elevates its expression (51). Similarly, Zhang et al (52) found that ALKBH5 was significantly overexpressed in glial stem cell-like cells (GSCs) and the interference of ALKBH5 could inhibit the proliferation of GSCs. In addition, the study also found that lncRNA FOXM1-AS promoted the interaction between ALKBH5 and FOXM1, indicating that m6A demethylase ALKBH5 acted as an oncogene in glioma. Recently, low expression of ALKBH5 in pancreatic cancer cell lines was found to promote the m6A demethylation of lncRNA KCNK15-AS1, resulting in a decreased ability of cancer invasion and metastasis (53). This provided a new direction for the diagnosis and treatment of pancreatic cancer.
In summary, further studies are required to investigate whether ALKBH5 is associated with the occurrence and development of other types of cancer and whether these key demethylation modifications are associated with the stability, translation, and alternative splicing of mRNA.
mRNA readers
The term, mRNA readers, refers to proteins that can specifically bind to mRNA with m6A methylation. The YTH domain is the marker of m6A binding protein on mRNA. Their affinity with m6A methylated mRNA is higher than that of unmethylated mRNA (54). The carboxyl terminal domain of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) selectively binds to the m6A modified mRNA, which assists the YTHDF2-mRNA complex to move to the RNA decay site of the cell, thus inducing the degradation of mRNA. The degradation of mRNA plays an important role in stem cell differentiation by regulating key pluripotent factors (55). In different situations, the YTH protein can interact with different subsets of the m6A locus and induce different effects on gene expression. Insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) is another m6A reader using the Khomlog (KH) domain to selectively bind m6A modified RNA and promote mRNA translation, which is different from proteins with the YTH domain (56). This discovery increased the understanding of the mechanism and function of the m6A binding protein. In addition, m6A modification could destroy the complementary pairing of nucleotides, improve the accessibility of single-stranded RNA motifs, and promote the recognition of m6A binding proteins heterogeneous nuclear ribonucleoprotein C and G.
YT521-B homology
The YTH domain recognizes m6A methylation in a methylation-dependent manner (57). A total of five proteins in the human body contain YTH domains. YTHDC1 can regulate the expression of mRNA in the nucleus by affecting the alternative splicing of mRNA precursors (58). Zhao et al (35) found that the expression of YTHDF1 was significantly increased in patients with advanced HCC. In addition, potential target genes regulated by the YTHDF1 protein may be associated with the cell cycle of the tumor, degradation of different amino acids and metabolism of various lipids. Li et al (59) reported that overexpression of miR-493-3p in YTHDF2 knockdown prostate cancer cell lines promoted m6A modification and thereby inhibited the proliferation and migration of the cancer cells. These findings lay a foundation for further investigation of the biological function of m6A and RNA epigenetics and provide a new direction for investigating the underlying mechanism of cancer development. Currently, the role of YTH family members in m6A methylation has become a hot topic, which provides novel approaches for investigating cancer-related mechanisms.
Eukaryotic initiation factors (eIF3). There are numerous and complex eIFs. Up to now, a total of 13 eIFs have been identified (60). eIF3 is the most complex factor in eIF translation and plays an important role in the initiation of protein translation. Li et al (61) first found that eIF3e was an independent prognostic factor for overall survival and disease-free survival time in patients with colon cancer. Downregulation of eIF3e expression could inhibit proliferation and promote apoptosis of colon cancer cells. Furthermore, the interaction between METTL-3 and eIF3h could increase mRNA translation and form dense polyribosomes, which was necessary for carcinogenic transformation (62). The study by Chao et al (39) revealed the regulatory mechanism of protein translation based on the mRNA cycle and indicated that METTL-3-eIF3h could be a potential therapeutic target for patients with lung cancer.
Detection methods of m6A methylation
In the early days, due to the limitation of technology, researchers could not detect m6A methylation sites. As m6A methylation of RNA does not affect its reverse transcription and it cannot be specifically cleaved, like M7G methylation, it is very difficult to identify the m6A site in the initial study (63). However, with the emergence of second-generation sequencing (seq), two techniques, screening m6A methylation site-m6A-seq (64) and methylated RNA immunoprecipitation sequencing (MeRIP-seq) have been developed (65). These methods were designed to capture RNA fragments with m6A methylation using co-immunoprecipitation then identify the sequences by second-generation sequencing. Subsequently, a multitude of m6A methylation sites were found, and researchers found up to 12,000 m6A signal peaks in >7,000 genes in humans and mice, all of which were enriched near the stop codon at the 3′ end (66). These sites were highly conserved in both humans and mice. This finding provided strong evidence for the post-transcriptional regulation of m6A methylation for gene expression and the modification may be associated with various genetic diseases (67,68). A limitation of this technique is that the RNA fragments captured are limited to 100–200 nucleotides and the technique cannot identify two very-close m6A sites, so this method cannot accurately identify the m6A methylation sites in the full transcriptome (69). In addition, a novel m6A modification was found at the 5′ end of mRNA (70). Asm6A modification has the same methyl site with m6A modification, both m6A-seq and MeRIP-seq may misinterpret this modification as m6A modification.
Based on the aforementioned limitations, the detection technology was improved by researchers. In 2015, three laboratories reported that the application of purple diplomatic co-immunoprecipitation could accurately capture m6A methylation sites on a single base of RNA, which is the core technology of m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) (69), photo-cross-linking-m6A-seq (71), and m6A-CLIP (or UV-CLIP) (72). Another technique for detecting m6A methylation site is m6A-LAIC-seq, which introduces spike-in-RNAs as an internal reference on the basis of m6A-seq to calculate the m6A methylation level of each gene in the full transcriptome (73). The disadvantage of this method is that a single m6A methylation site cannot be detected. In addition to Qualcomm sequencing, the methods detecting the m6A methylation site of a single gene are also important. The most famous one is site-specific cleavage and radioactive-labeling followed by ligation-assisted extraction and thin-layer chromatography (SCARLET) test (74), which can accurately detect a single m6A methylation site in mRNA and lncRNA, and calculate the m6A methylation level of the whole RNA (73). SCARLET is a low-throughput test with high expenses; however, its high accuracy makes it a common method for testing the accuracy of high-throughput detection of m6A methylation sites. In addition, SCARLET can be used to detect other types of epigenetic modifications of RNA, such as M5C modification and ψ modification (75). Fluorescence quantitative PCR can also be used to detect the level of m6A methylation. Golovina et al (76) found that different m6A methylation levels in the same RNA will produce different melting curves under fluorescence quantitative PCR detection, which is due to the different melting temperatures of the RNA-DNA complex with different m6A methylation levels. Therefore, Golovina et al proposed a high-resolution melting detection method, which could detect the alternation of the known m6A methylation level in RNA. However, the experiments were only performed with ribosomal RNA, total RNA and snRNA, so whether this technology can be extended to other types of RNA remains to be verified.
With the progress of high-throughput sequencing and antibody-specific enrichment technology, a new detection method, methylated RNA immunoprecipitation sequencing (MeRIP-seq), was developed with the advantage of identifying almost all m6A modifications in different types of RNA, such as mRNA (77), lncRNA (78) and circular RNA (79). In MeRIP-seq, specific antibody of m6A is used to extract co-immunoprecipitated RNA fragments, which are further identified using high-throughput sequencing (80). Then, the m6A modification can be systematically investigated in combination with bioinformatics analysis. However, the main limitation of MeRIP-seq is that MeRIP-seq can only identify hypermethylated regions of the RNA, but cannot locate a certain m6A site (81).
Subsequently, a novel sequencing method, miCLIP-seq, was developed to identify the specific site of m6A modification. Apart from the application of m6A antibodies to identify and enrich m6A modification, miCLIP-seq also uses UV cross-linking method to identify m6A modification at the single-base level in the whole genome. Therefore, miCLIP-seq can efficiently detect the m6A residue with high resolution and perform m6A cluster analysis on the whole RNA, which provides a novel technique to investigate the unique epigenetic trait of RNA. Furthermore, miCLIP can also detect the m6A modification in a class of small non-coding RNA, such as small nucleolus RNA, which cannot be obtained using previous techniques. High-throughput sequencing technology has improved and is effective, but fluorescence quantitative detection is still one of the most economical and convenient molecular detection methods. There is clear importance to develop fluorescence quantitative PCR for m6A detection. With the gradual improvement of the detection methods of m6A methylation sites, a deeper understanding of m6A methylation will develop, which lays a solid foundation for the study into the association between m6A methylation and various diseases, particularly cancer. Table II lists the characteristics of five detection methods.
Prediction methods of m6A methylation sites
As the detection of the m6A methylation site is expensive and time consuming, bioinformatics prediction has been used to improve the research efficiency with high cost-effectiveness. In recent years, bioinformatics has developed rapidly and been widely used in molecular biology research. The following methods can assist with the prediction of the methylation sites of m6A more effectively. Yu-Chen et al (82) first proposed the use of the Hidden Markov Model (HMM) to predict the residual sites around known sites. Li et al (83) developed the pRNAm-PC method to predict loci faster and was more stable. In addition, Chen et al (84) developed the iRNA-Methyl method. Based on these, Jia et al (85) developed the RNA-methylPred method, which is more stable and efficient than the former. After that, Li et al (83) proposed an improved Target m6A method, but this method could only predict the methylation site of m6A in the primary RNA sequence. On the other hand, Zhou et al (86) synthesized several mathematical models and proposed the sequence-based RNA adenosine methylation site predictor (SRAMP) method, which could effectively predict m6A methylation sites in mammalian RNA. Recently, an online database called, RMBase-V2.0, has been established (http://rna.sysu.edu.cn/rmbase/), which contains a number of RNA epigenetic modification sequence data of 13 species, including a high amount of data on m6A methylation sites.
Association between m6A modification and malignancies
m6A modification and breast cancer
Breast cancer stem cells (BCSCs) can proliferate indefinitely via self-renewal and forming recurrent or metastatic tumors (87). In the hypoxic tumor microenvironment, ALKBH5 could reduce m6A methylation in NANOG mRNA, increase the expression of NANOG mRNA and mediate the enrichment of BCSCs in a HIF-dependent manner (51). Zinc-finger protein 217 (ZFP217) and ALKBH5 play complementary roles in regulating m6A methylation in RNA (18). Hypoxia-induced ZNF217 inhibited m6A methylation of NANOG mRNA, whereas ALKBH5 induced m6A demethylation. Taken together, they can increase the expression of NANOG mRNA and protein and enrich BCSCs. In addition, ZFP217 and ALKBH5 were associated with a more malignant phenotype of breast cancer by inhibiting m6A methyltransferase-related modifiers or inducing HIF-dependent hypoxia (88). A recent study reported that m6A modification regulated the expression of early polyadenylation (premature polyadenylation; PPA), which blocked the expression of tumor suppressor genes and lead to carcinogenesis (89). In breast cancer cells, premature polyadenylation causes oncogenic truncations of the tumor suppressor genes MAGI3 (90), LATS1 (91) and BRCA1 (92). The activation and truncation of PPA in tumor suppressor genes was regulated by m6A modification. Compared with that in normal breast cells, m6A methylation, activated by PPA significantly, was decreased in tumor suppressor gene-related exons. However, there are no conclusions on how breast cancer cells regulate the level of m6A in exons to trigger PPA.
m6A modification and colon cancer
As an ATP-dependent RNA helicase and a member of the YTH family, YTHDF2 promoted initial translation by unlocking the 5′-UTR of mRNA, and the transcription and translation of metastasis-related factors by inducing m6A methylation, thereby enhancing the metastasis of cancer cells (93). In colon cancer, YTHDF2 promoted metastasis by promoting the translation of HIF-1α. Knockdown of the YTHDF2 gene could reduce the expression level of metastasis-related genes, such as HIF-1α and inhibit the metastasis of colon cancer cells in vitro and In vivo (94). In addition, the expression level of YTHDF2 was positively associated with the stage of colon cancer. At present, few studies have identified the function and target of YTHDF2 in the progression and metastasis of colon cancer. However, these findings will provide new insights into the role of RNA demethylase in tumorigenesis.
m6A modification and liver cancer
Hou et al (95) have revealed that YTHDF2 was positively associated with the malignant grade of HCC. miR-145 could increase the level of m6A methylation by targeting the 3′-UTR of YTHDF2 mRNA in HCC cells, leading to the malignant progression of HCC. In addition, YTHDF1 was highly expressed in human HCC tissues and associated with the regulation of the cell cycle and metabolism of HCC cells. Furthermore, the deletion of m6A methylation was associated with the metastasis of HCC with the downregulation of METTL-14. In HCC, METTL-3 mediated the methylation of m6A in the mRNA of the chromosome (or critical) region in DiGeorge syndrome (96). METTL-14 could significantly upregulate the level of miR-126 modified by m6A methylation, thus promoting the maturation of miR-126 and inhibiting the metastasis of HCC cells (97). At present, the mechanism of how METTL-14 has a low expression in liver cancer cells remains unclear. More in-depth investigation is required to clarify the structure and biological function of METTL-14 in cancer to determine whether METTL-14 can be used as a therapeutic target for the treatment of liver cancer. However, the interaction between METTL-14 and YTHDF1/2 with miRNA still provides clues for identifing new approaches to treat liver cancer.
m6A modification and pancreatic cancer
The role of METTL-14 in pancreatic cancer has also been confirmed. The methylase, METTL-14 was highly expressed in pancreatic cancer tissues. METTL-14 could promote the proliferation, invasion, and metastasis of pancreatic cancer cells by increasing the level of m6A methylation, inhibiting the expression of miR-1-3p, and activating the mitogen-activated protein kinase (MAPK) pathway (98). In addition, a new mechanism of lncRNA with m6A methylation was found. ALKBH5 inhibited the progression of pancreatic cancer by promoting m6A demethylation of lncRNA potassium two-pore domain channel subfamily K member 15 (KCNK15) and WNT1-induced signal pathway protein 2 (WISP2) antisense lncCNK15-AS1 (53). This finding reveals a new area for investigating the role of lncRNA methylation in cancer development.
m6A modification and hematopoietic tumor
WTAP, as an m6A demethylase, plays a carcinogenic role in AML. Both In vivo and in vitro research has proved that WTAP was associated with cell transformation and all-trans retinoic acid (ATRA)-mediated leukemia cell differentiation (48). In addition, METTL-3 inhibited the differentiation of hematopoietic stem/progenitor cell in patients with AML by inducing m6A methylation, which maintained the undifferentiated phenotype of the leukemia cells and promoted the occurrence of AML. On the other hand, the knockdown or deletion of METTL-3 could activate a translation process to promote cell differentiation and apoptosis, leading to the suppression of leukemia cells without affecting normal hematopoietic cells (17). Similarly, METTL-14 plays a key role in both normal myelopoiesis and pathogenesis of AML (8). METTL-14 could block normal myeloid differentiation and promote malignant bone marrow formation by mediating m6A methylation. These studies provide new insights into the molecular mechanism of hematological tumorigenesis, suggesting that inhibition of METTL-3/14 may be used as a strategy for the treatment of malignant myeloid tumors.
m6A modification and endometrial carcinoma
In 2018, a study found that m6A methylation in mRNA played a crucial role in endometrial carcinogenesis with the activation of protein kinase B (PKB) signal (99). m6A methylation reduced the expression of PKB negative regulator PH domain and leucine-rich repetitive protein phosphatase 2, whereas the expression of the positive PKB regulator mammalian target of rapamycin c2 was elevated, which promoted the proliferation and invasion endometrial cancer cells (49).
m6A modification and cervical cancer
Previous studies have found that a low level of m6A was associated with the occurrence of cervical cancer. In addition, the decrease in m6A level was positively associated with The International Federation of Gynecology and Obstetrics stage, tumor size, degree of differentiation, lymph node invasion and tumor recurrence (100). The results suggested that m6A methylation site in mRNA may serve as a potential therapeutic target for cervical cancer and could be used as an independent prognostic factor for predicting disease-free survival and overall survival times in patients with cervical cancer (101,102).
m6A modification and gastric cancer
In gastric cancer, the expression level of ALKBH5, a m6A ‘eraser’, was significantly decreased in highly invasive diffuse gastric adenocarcinoma compared with that in adjacent tissues. The knockdown of ALKBH5 could decrease the mRNA and protein expression levels of E-cadherin and increase the expression level of interstitial markers, such as snail (103) and N-cadherin (104). Further investigation showed that the downregulation of ALKBH5 could decrease the ability of mRNA demethylation and promote the methylation level, which reduced the stability of E-cadherin mRNA and promoted the invasion of tumor cells. Furthermore, ALKBH5, as a tumor suppressor gene in gastric cancer (105), could suppress EMT, migration, and invasion of gastric cancer cells by inhibiting the mRNA and protein expression levels of MMP-2 and MMP-9. In addition, WTAP was found to play an important role in the progression and metastasis of gastric cancer, and was associated with poor differentiation, lymph node metastasis, high TNM stages and poor prognosis (106). M6A may also be an important molecular marker for monitoring gastric cancer. Furthermore, the expression level of METTL-3 was positively associated with the prognosis, tumor grade and tumor stage in patients with gastric cancer (107). In addition, METTL-3 was associated with the mRNA and protein expression levels of a-smooth muscle actin to regulate the proliferation and migration of gastric cancer cells, which could be a potential target for the treatment of gastric cancer in the future (108,109).
m6A modification and other types of cancer
They regulate the level of m6A through direct or indirect modification and participate in tumor progression. WTAP enhanced the expression of marrow zinc finger 1 (MZF1) by reducing the level of m6A and destabilizing MZF1 mRNA in bone, thus promoting the progression of lung squamous cell carcinoma. YTHDF2 and miR-495 inhibited the progression of prostate cancer by indirectly downregulating the level of m6A methylation (110). ALKBH5 maintained the expression level of fork box protein M1 mRNA by promoting m6A demethylation, which retained the tumorigenicity of glioblastoma stem cells (52). The aforementioned studies revealed the importance of m6A modification in different types of cancer. The dynamic change of m6A methylation has various regulatory effects on cancer cells (111). By revealing the previously unidentified regulation mechanism in tumors, further studies will provide bases for exploring the pathogenesis of tumors and developing new potential targets for cancer treatment (112,113).
Conclusions
Since m6A methylation plays an important role in numerous types of malignant tumor, m6A modification could be used as a diagnostic/prognostic target. Due to the effect of various related factors, the results of from several researchers are sometimes contradictory. This requires more multicenter and large-scale research for further investigation, thus laying the foundation for accurate treatment of human tumors.
Acknowledgements
The authors would like to thank Mrs. Wei Zhou and Mrs. Keyan Wu (Department of Cell Biology, School of Medicine of Yangzhou University) for their help with the literature search.
Funding
No funding was received.
Availability of data and materials
Not applicable.
Author's contributions
YZ conceived and designed this study. The literature search was carried out by JY. ZT and JZ were involved in drafting the manuscript or revising it critically for important intellectual content, in addition they resolved any disagreements. The manuscript was drafted by YZ and WS. Manuscript revisions and modifications were carried out by YZ. Final changes were made by JY and WS. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for participation
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
m6A |
N6-methyladenosine |
|
FTO |
fat mass and obesity-associated protein |
|
ALKBH5 |
AlkB homologous protein 5 |
|
YTHDF2 |
YTH N6-methyladenosine RNA binding protein 2 |
|
eIFs |
eukaryotic initiation factors |
|
MeRIP-Seq |
methylated RNA immunoprecipitation sequencing |
|
miCLIP-seq |
m6A individual nucleotide resolution cross-linking and immunoprecipitation |
|
HCC |
hepatocellular carcinoma |
|
RCC |
renal cell carcinoma |
|
SAM |
S-adenosylmethionine |
|
PDAC |
pancreatic ductal adenocarcinoma |
|
CSCC |
cervical squamous cell carcinoma |
|
HIF |
hypoxia-inducible factors |
|
IGF2BP2 |
insulin like growth factor 2 mRNA binding protein 2 |
|
snRNA |
small nuclear RNA |
|
BCSCs |
breast cancer stem cells |
|
ZFP217 |
zinc-finger protein 217 |
References
|
Neal DE, Metcalfe C, Donovan JL, Lane JA, Davis M, Young GJ, Dutton SJ, Walsh EI, Martin RM, Peters TJ, et al: Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the protecT randomised controlled trial according to treatment received. Eur Urol. 77:320–330. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Enane FO, Saunthararajah Y and Korc M: Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells. Cell Death Dis. 9:9122018. View Article : Google Scholar : PubMed/NCBI | |
|
Li J, Yang X, Qi Z, Sang Y, Liu Y, Xu B, Liu W, Xu Z and Deng Y: The role of mRNA m 6 A methylation in the nervous system. Cell Biosci. 9:662019. View Article : Google Scholar : PubMed/NCBI | |
|
Lv Z, Sun L, Xu Q, Xing C and Yuan Y: Joint analysis of lncRNA m6A methylome and lncRNA/mRNA expression profiles in gastric cancer. Cancer Cell Int. 20:4642020. View Article : Google Scholar : PubMed/NCBI | |
|
Pan X, Hong X, Li S, Meng P and Xiao F: METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner. Exp Mol Med. 53:91–102. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, et al: m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature. 548:338–342. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Liu K and Chen W: iMRM: A platform for simultaneously identifying multiple kinds of RNA modifications. Bioinformatics. 36:3336–3342. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J, Shen C, Hu C, et al: METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell. 22:191–205.e9. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Chen M, Wei L, Law CT, Tsang FH, Shen J, Cheng CL, Tsang LH, Ho DW, Chiu DK, Lee JM, et al: RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 67:2254–2270. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Chen J, Zhang YC, Huang C, Shen H, Sun B, Cheng X, Zhang YJ, Yang YG, Shu Q, Yang Y and Li X: m6A regulates neurogenesis and neuronal development by modulating histone methyltransferase Ezh2. Genomics Proteomics Bioinformatics. 17:154–168. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Lin S, Choe J, Du P, Triboulet R and Gregory RI: The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 62:335–345. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Shi H, Wei J and He C: Where, when, and how: Context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 74:640–650. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Liu N, Zhou KI, Parisien M, Dai Q, Diatchenko L and Pan T: N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 45:6051–6063. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Liu N, Dai Q, Zheng G, He C, Parisien M and Pan T: N (6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 518:560–564. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Lan Q, Liu PY, Haase J, Bell JL, Hüttelmaier S and Liu T: The critical role of RNA m6A methylation in cancer. Cancer Res. 79:1285–1292. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, et al: Promoter-bound METTL3 maintains myeloid leukaemia by m 6 A-dependent translation control. Nature. 552:126–131. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, et al: The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 23:1369–1376. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang C, Zhi WI, Lu H, Samanta D, Chen I, Gabrielson E and Semenza GL: Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217-and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget. 7:64527–64542. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, Liu Y, Zhang X, Zhang W and Ye L: HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 415:11–19. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Taketo K, Konno M, Asai A, Koseki J, Toratani M, Satoh T, Doki Y, Mori M, Ishii H and Ogawa K: The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol. 52:621–629. 2018.PubMed/NCBI | |
|
Sun Y, Li S, Yu W, Zhao Z, Gao J, Chen C, Wei M and Liu L: 1981O-The m(6)A methyltransferase METTL3 promotes gastric cancer progression through facilitating primary microRNA maturation. Ann Oncol. 30:v7972019. View Article : Google Scholar | |
|
Liu S, Li Q, Li G, Zhang Q, Zhuo L, Han X, Zhang M, Chen X, Pan T, Yan L, et al: The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene. Cell Death Dis. 11:9692020. View Article : Google Scholar : PubMed/NCBI | |
|
Li X, Tang J, Huang W, Wang F, Li P, Qin C, Qin Z, Zou Q, Wei J, Hua L, et al: The M6A methyltransferase METTL3: Acting as a tumor suppressor in renal cell carcinoma. Oncotarget. 8:96103–96116. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Robinson M, Shah P, Cui YH and He YY: The role of dynamic m6A RNA methylation in photobiology. Photochem Photobiol. 95:95–104. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Du Y, Hou G, Zhang H, Dou J, He J, Guo Y, Li L, Chen R, Wang Y, Deng R, et al: SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. Nucleic Acids Res. 46:5195–5208. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Selberg S, Blokhina D, Aatonen M, Koivisto P, Siltanen A, Mervaala E, Kankuri E and Karelson M: Discovery of small molecules that activate RNA methylation through cooperative binding to the METTL3-14-WTAP complex active site. Cell Rep. 26:3762–3771.e5. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, Wang TT, Xu QG, Zhou WP and Sun SH: METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary MicroRNA processing. Hepatology. 65:529–543. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ruszkowska A: METTL16, methyltransferase-like protein 16: Current insights into structure and function. Int J Mol Scis. 22:21762021. View Article : Google Scholar | |
|
Warda AS, Kretschmer J, Hackert P, Lenz C, Urlaub H, Höbartner C, Sloan KE and Bohnsack MT: Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Rep. 18:2004–2014. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Detich N, Hamm S, Just G, Knox JD and Szyf M: The methyl donor S-Adenosylmethionine inhibits active demethylation of DNA: A candidate novel mechanism for the pharmacological effects of S-Adenosylmethionine. J Biol Chem. 278:20812–20820. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Shima H, Matsumoto M, Ishigami Y, Ebina M, Muto A, Sato Y, Kumagai S, Ochiai K, Suzuki T and Igarashi K: S-Adenosylmethionine synthesis is regulated by selective N6-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep. 21:3354–3363. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Schwartz S, Mumbach MR, Jovanovic M, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, et al: Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 8:284–296. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al: Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24:177–189. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Sorci M, Ianniello Z, Cruciani S, Larivera S, Ginistrelli LC, Capuano E, Marchioni M, Fazi F and Fatica A: METTL3 regulates WTAP protein homeostasis. Cell Death Dis. 9:7962018. View Article : Google Scholar : PubMed/NCBI | |
|
Xi Z, Xue Y, Zheng J, Liu X, Ma J and Liu Y: WTAP expression predicts poor prognosis in malignant glioma patients. J Mol Neurosci. 60:131–136. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Li BQ, Huang S, Shao QQ, Sun J, Zhou L, You L, Zhang TP, Liao Q, Guo JC and Zhao YP: WT1-associated protein is a novel prognostic factor in pancreatic ductal adenocarcinoma. Oncol Lett. 13:2531–2538. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Tang J, Wang F, Cheng G, Si S, Sun X, Han J, Yu H, Zhang W, Lv Q, Wei JF and Yang H: Wilms' tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability. J Exp Clin Cancer Res. 37:402018. View Article : Google Scholar : PubMed/NCBI | |
|
Su R, Li Z, Weng H, Weng X and Chen J: FTO Plays an oncogenic role in acute myeloid leukemia As a N6-methyladenosine RNA demethylase. Blood. 128:2706. 2016. View Article : Google Scholar | |
|
Chao Y, Shang J and Ji W: ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia. Biochem Biophys Res Commun. 521:499–506. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Kusinska R, Górniak P, Pastorczak A, Fendler W, Potemski P, Mlynarski W and Kordek R: Influence of genomic variation in FTO at 16q12. 2, MC4R at 18q22 and NRXN3 at 14q31 genes on breast cancer risk. Mol Biol Rep. 39:2915–2919. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L, Wang Y, Li X, Xiong XF, Wei B, et al: RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 18:462019. View Article : Google Scholar : PubMed/NCBI | |
|
Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG and He C: N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 7:885–887. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Tian R, Zhang S, Sun D, Bei C, Li D, Zheng C, Song X, Chen M, Tan S, Zhu X and Zhang H: M6A demethylase FTO plays a tumor suppressor role in thyroid cancer. DNA Cell Biol. 39:2184–2193. 2020. View Article : Google Scholar | |
|
Gaudet MM, Yang HP, Bosquet JG, Healey CS, Ahmed S, Dunning AM, Easton DF, Spurdle AB, Ferguson K, O'Mara T, et al: No association between FTO or HHEX and endometrial cancer risk. Cancer Epidemiol Biomarkers Prev. 19:2106–2109. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Li Y, Zheng D, Wang F, Xu Y, Yu H and Zhang H: Expression of demethylase genes, FTO and ALKBH1, is associated with prognosis of gastric cancer. Dig Dis Sci. 64:1503–1513. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Tsuruta N, Tsuchihashi K, Ohmura H, Yamaguchi K, Ito M, Ariyama H, Kusaba H, Akashi K and Baba E: RNA N6-methyladenosine demethylase FTO regulates PD-L1 expression in colon cancer cells. Biochem Biophys Res Commun. 530:235–239. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Hernández-Caballero ME and Sierra-Ramírez JA: Single nucleotide polymorphisms of the FTO gene and cancer risk: An overview. Mol Biol Rep. 42:699–704. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, et al: FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell. 31:127–141. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou S, Bai ZL, Xia D, Zhao ZJ, Zhao R, Wang YY and Zhe H: FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation. Mol Carcinog. 57:590–597. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Xu C, Liu K, Tempel W, Demetriades M, Aik W, Schofield CJ and Min J: Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. J Biol Chem. 289:17299–17311. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X and Semenza GL: Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 113:E2047–E2056. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, et al: m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 31:591–606.e6. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P, Liu D, Tian L, Yin J, Jiang K and Miao Y: ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation. Cell Physiol Biochem. 48:838–846. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Lee Y, Choe J, Park OH and Kim YK: Molecular mechanisms driving mRNA degradation by m6A modification. Trends Genet. 36:177–188. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Sheng H, Li Z, Su S, Sun W, Zhang X, Li L, Li J, Liu S, Lu B, Zhang S and Shan C: YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation. Carcinogenesis. 41:541–550. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Li Z, Zhang Y, Ramanujan K, Ma Y, Kirsch DG and Glass DJ: Oncogenic NRAS, required for pathogenesis of embryonic rhabdomyosarcoma, relies upon the HMGA2-IGF2BP2 pathway. Cancer Res. 73:3041–3050. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Liao S, Sun H and Xu C: YTH domain: A family of N6-methyladenosine (m6A) readers. Genomics Proteomics Bioinformatics. 16:99–107. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, Sun HY, Li A, Ping XL, Lai WY, et al: Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell. 61:507–519. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Li J, Meng S, Xu M, Wang S, He L, Xu X, Wang X and Xie L: Downregulation of N6-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N6-methyladenosine levels. Oncotarget. 9:3752–3764. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Bhardwaj U, Powell P and Goss DJ: Eukaryotic initiation factor (eIF)3 mediates barley yellow dwarf viral mRNA 3′-5′UTR interactions and 40S ribosomal subunit binding to facilitate cap-independent translation. Nucleic Acids Res. 47:6225–6235. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Li Z, Lin S, Jiang T, Wang J, Lu H, Tang H, Teng M and Fan J: Overexpression of eIF3e is correlated with colon tumor development and poor prognosis. Int J Clin Exp Pathol. 7:6462–6474. 2014.PubMed/NCBI | |
|
Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J, Du P, Kim W, Tang S, Sliz P, et al: mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature. 561:556–560. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, et al: Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 485:201–206. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Antanaviciute A, Baquero-Perez B, Watson CM, Harrison SM, Lascelles C, Crinnion L, Markham AF, Bonthron DT, Whitehouse A and Carr IM: m6aViewer: Software for the detection, analysis, and visualization of N6-methyladenosine peaks from m6A-seq/ME-RIP sequencing data. RNA. 23:1493–1501. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang SY, Zhang SW, Fan XN, Zhang T, Meng J and Huang Y: FunDMDeep-m6A: Identification and prioritization of functional differential m6A methylation genes. Bioinformatics. 35:i90–i98. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR: Comprehensive analysis of mRNA methylation reveals enrichment in 3′UTRs and near stop codons. Cell. 149:1635–1646. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Chandola U, Das R and Panda B: Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease. Brief Funct Genomics. 14:169–179. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, Yang C and Chen Y: The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 6:742021. View Article : Google Scholar : PubMed/NCBI | |
|
Linder B, Grozhik AV, Olarerin-George AO, Meydan C, Mason CE and Jaffrey SR: Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat Methods. 12:767–772. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur JJ, Chen Q, et al: Reversible methylation of m6Am in the 5′cap controls mRNA stability. Nature. 541:371–375. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Chen K, Lu Z, Wang X, Fu Y, Luo GZ, Liu N, Han D, Dominissini D, Dai Q, Pan T, et al: High-resolution N(6)-methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. Angew Chem Int Ed Engl. 54:1587–1590. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, et al: A majority of m6A residues are in the last exons, allowing the potential for 3′UTR regulation. Genes Dev. 29:2037–2053. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Molinie B, Wang J, Lim KS, Hillebrand R, Lu ZX, Van Wittenberghe N, Howard BD, Daneshvar K, Mullen AC, Dedon P, et al: m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome. Nat Methods. 13:692–698. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Liu N, Parisien M, Dai Q, Zheng G, He C and Pan T: Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA. 19:1848–1856. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Li X, Zhu P, Ma S, Song J, Bai J, Sun F and Yi C: Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat Chem Biol. 11:592–597. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Golovina AY, Dzama MM, Petriukov KS, Zatsepin TS, Sergiev PV, Bogdanov AA and Dontsova OA: Method for site-specific detection of m6A nucleoside presence in RNA based on high-resolution melting (HRM) analysis. Nucleic Acids Res. 42:e272014. View Article : Google Scholar : PubMed/NCBI | |
|
Wang M, Liu J, Zhao Y, He R, Xu X, Guo X, Li X, Xu S, Miao J, Guo J, et al: Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer. Mol Cancer. 19:1302020. View Article : Google Scholar : PubMed/NCBI | |
|
Xue L, Li J, Lin Y, Liu D, Yang Q, Jian J and Peng J: m6A transferase METTL3-induced lncRNA ABHD11-AS1 promotes the Warburg effect of non-small-cell lung cancer. J Cell Physiol. 236:2649–2658. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Wang H, Xi F, Wang H, Han X, Wei W, Zhang H, Zhang Q, Zheng Y, Zhu Q, et al: Profiling of circular RNA N6-methyladenosine in moso bamboo (Phyllostachys edulis) using nanopore-based direct RNA sequencing. J Integr Plant Biol. 62:1823–1838. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Z, Wang Q, Zhang M, Zhang W, Zhao L, Yang C, Wang B, Jiang K, Ye Y, Shen Z and Wang S: Comprehensive analysis of the transcriptome-wide m6A methylome in colorectal cancer by MeRIP sequencing. Epigenetics. 16:425–435. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Han Z, Yang B, Wang Q, Hu Y, Wu Y and Tian Z: Comprehensive analysis of the transcriptome-wide m6A methylome in invasive malignant pleomorphic adenoma. Cancer Cell Int. 21:1422021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang YC, Zhang SW, Liu L, Liu H, Zhang L, Cui X, Huang Y and Meng J: Spatially enhanced differential RNA methylation analysis from affinity-based sequencing data with hidden Markov model. Biomed Res Int. 2015:8520702015.PubMed/NCBI | |
|
Li GQ, Liu Z, Shen HB and Yu DJ: TargetM6A: Identifying N6-Methyladenosine sites from RNA sequences via position-specific nucleotide propensities and a support vector machine. IEEE Trans Nanobioscience. 15:674–682. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Chen W, Feng P, Ding H, Lin H and Chou KC: iRNA-Methyl: Identifying N(6)-methyladenosine sites using pseudo nucleotide composition. Anal Biochem. 490:26–33. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Jia CZ, Zhang JJ and Gu WZ: RNA-MethylPred: A high-accuracy predictor to identify N(6)-methyladenosine in RNA. Anal Biochem. 510:72–75. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou Y, Zeng P, Li YH, Zhang Z and Cui Q: SRAMP: Prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features. Nucleic Acids Res. 44:e912016. View Article : Google Scholar : PubMed/NCBI | |
|
Woosley AN, Dalton AC, Hussey GS, Howley BV, Mohanty BK, Grelet S, Dincman T, Bloos S, Olsen SK and Howe PH: TGFβ promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis. Oncogene. 38:3794–3811. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Song T, Yang Y, Wei H, Xie X, Lu J, Zeng Q and Peng J, Zhou Y, Jiang S and Peng J: Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation. Nucleic Acids Res. 47:6130–6144. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao X and Cui L: Development and validation of a m6A RNA methylation regulators-based signature for predicting the prognosis of head and neck squamous cell carcinoma. Am J Cancer Res. 9:2156–2169. 2019.PubMed/NCBI | |
|
Du S, Hu W, Zhao YI, Zhou H, Wen W, Xu M, Zhao P and Liu K: Long non-coding RNA MAGI2-AS3 inhibits breast cancer cell migration and invasion via sponging microRNA-374a. Cancer Biomark. 24:269–277. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Ercolani C, Di Benedetto A, Terrenato I, Pizzuti L, Di Lauro L, Sergi D, Sperati F, Buglioni S, Ramieri MT, Mentuccia L, et al: Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy. Cancer Biol Ther. 18:339–346. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ni TK and Kuperwasser C: Abstract 4995: Premature polyadenylation causes oncogenic truncations of the tumor suppressor genes BRCA1, LATS1 and MAGI3 in breast cancer. Cancer Res. 77:49952017. | |
|
Tanabe A, Tanikawa K, Tsunetomi M, Takai K, Ikeda H, Konno J, Torigoe T, Maeda H, Kutomi G, Okita K, et al: RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett. 376:34–42. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao YL, Liu YH, Wu RF, Bi Z, Yao YX, Liu Q, Wang YZ and Wang XX: Understanding m6A function through uncovering the diversity roles of YTH domain-containing proteins. Mol Biotechnol. 61:355–364. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, Hu B, Zhou J, Zhao Z, Feng M, et al: YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 18:1632019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao M, Jia M, Xiang Y, Zeng Y, Yu W, Xiao B and Dai R: METTL3 promotes the progression of hepatocellular carcinoma through m6A-mediated up-regulation of microRNA-873-5p. Am J Physiol Gastrointest Liver Physiol. Jul 20–2020.(Epub ahead of print). doi: 10.1152/ajpgi.00161.2020. PubMed/NCBI | |
|
Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, Wang TT, Xu QG, Zhou WP and Sun SH: METTL14 suppresses the metastatic potential of HCC by modulating m6 A-dependent primary miRNA processing. Hepatology. 65:529–543. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Xu XD: Effects of N6-methylpurine(m6A) methyltransferase METTL14 on the proliferation, invasion and metastasis of pancreatic cancer and its mechanism. Huazhong Univ Sci Technol, (PhD Thesis), . 2017. | |
|
Liu J, Eckert MA, Harada BT, Liu SM, Lu Z, Yu K, Tienda SM, Chryplewicz A, Zhu AC, Yang Y, et al: m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 20:1074–1083. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang X, Li Z, Kong B, Song C, Cong J, Hou J and Wang S: Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer. Oncotarget. 8:98918–98930. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ma X, Li Y, Wen J and Zhao Y: m6A RNA methylation regulators contribute to malignant development and have a clinical prognostic effect on cervical cancer. Am J Transl Res. 12:8137–8146. 2020.PubMed/NCBI | |
|
Ji F, Lu Y, Chen S, Yu Y, Lin X, Zhu Y and Luo X: IGF2BP2-modified circular RNA circARHGAP12 promotes cervical cancer progression by interacting m6A/FOXM1 manner. Cell Death Discov. 7:2152021. View Article : Google Scholar : PubMed/NCBI | |
|
Lin X, Chai G, Wu Y, Chen F, Liu J, Luo G, Tauler J, Du J, Lin S, He C and Wang H: RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun. 10:20652019. View Article : Google Scholar : PubMed/NCBI | |
|
Huang GZ, Wu QQ, Zheng ZN, Shao TR, Chen YC, Zeng WS and Lv XZ: M6A-related bioinformatics analysis reveals that HNRNPC facilitates progression of OSCC via EMT. Aging (Albany NY). 12:11667–11684. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z and Zhao G: METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 18:1422019. View Article : Google Scholar : PubMed/NCBI | |
|
Li H, Su Q, Li B, Lan L, Wang C, Li W, Wang G, Chen W, He Y and Zhang C: High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour-associated T lymphocyte infiltration. J Cell Mol Med. 24:4452–4465. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Sun Y, Li S, Yu W, Zhao Z, Gao J, Chen C, Wei M, Liu T, Li L and Liu L: N6-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer. Cell Death Dis. 11:8362020. View Article : Google Scholar : PubMed/NCBI | |
|
Lin S, Liu J, Jiang W, Wang P, Sun C, Wang X, Chen Y and Wang H: METTL3 promotes the proliferation and mobility of gastric cancer cells. Open Med (Wars). 14:25–31. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Liu T, Yang S, Sui J, Xu SY, Cheng YP, Shen B, Zhang Y, Zhang XM, Yin LH, Pu YP and Liang GY: Dysregulated N6-methyladenosine methylation writer METTL3 contributes to the proliferation and migration of gastric cancer. J Cell Physiol. 235:548–562. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Du C, Lv C, Feng Y and Yu S: Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. J Exp Clin Cancer Res. 39:2232020. View Article : Google Scholar : PubMed/NCBI | |
|
Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, Cheng C, Li L, Pi J, Si Y, et al: The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 48:3816–3831. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Huang H, Weng H and Chen J: m(6)A modification in coding and non-coding RNAs: Roles and therapeutic implications in cancer. Cancer Cell. 37:270–288. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Ma S, Chen C, Ji X, Liu J, Zhou Q, Wang G, Yuan W, Kan Q and Sun Z: The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol. 12:1212019. View Article : Google Scholar : PubMed/NCBI |
