Skip to content
BY 4.0 license Open Access Published by De Gruyter Open Access November 30, 2023

METTL16 in human diseases: What should we do next?

  • Hui Zhang , Mengqi Yin EMAIL logo , Hua Huang , Gongfang Zhao and Mingliang Lu EMAIL logo
From the journal Open Medicine


METTL16 is a class-I methyltransferase that is responsible for depositing a vertebrate-conserved S-adenosylmethionine site. Since 2017, there has been a growing body of research focused on METTL16, particularly in the field of structural studies. However, the role of METTL16 in cell biogenesis and human diseases has not been extensively studied, with limited understanding of its function in disease pathology. Recent studies have highlighted the complex and sometimes contradictory role that METTL16 plays in various diseases. In this work, we aim to provide a comprehensive summary of the current research on METTL16 in human diseases.

1 Introduction

m6A modification is considered the most prevalent RNA modification in mammalian cells, emerging in both coding RNAs and non-coding RNAs [15]. This epi-transcriptional modification is known to promote the initiation and progression of many human diseases [68]. As is widely understood, m6A modification is regulated by writers, readers, and erasers, and exerts its effects by influencing RNA splicing, stability, transcription, translation, and decay [813]. To date, many m6A writers, such as METTL3, METTL14, WTAP, KIAA1429, and RBM15, have been thoroughly investigated, while the role of METTL16 in this process remains poorly understood.

METTL16 belongs to the class-I methyltransferase family, which has a vertebrate conserved S-adenosylmethionine (SAM) site [1416]. Structural studies over the past few decades have confirmed that METTL16 consists of 562 amino acids, involving to seven beta-strands in the Rossmann fold. The quaternary structure of METTL16 is formed by an N-terminal methyltransferase domain (MTD) and two C-terminal vertebrate-conserved regions (VCRs), the MTD and the two VCRs are flanked by two disordered regions [14,17,18]. Accumulated studies have shown that METTL16 can exist as both a homodimer and a monomer [17,19], and is found in both the cytoplasm and nucleus [15]. METTL16 directly binds to target RNA that possesses a specific sequence and stem-loop structure, and also binds directly to the translation initiation complex (TIC) to regulate translation [5,17,2022]. Studies have shown that METTL16 is closely related to almost all types of RNAs, as well as many RNA regulators and effectors [2325]. Other studies have determined that METTL16 is also involved in maintaining SAM homeostasis [17,20]. Particularly, METTL16 can directly interact with ribosomal RNA to enhance translation, which distinguishes it from other METTL members such as METTL3 [22].

Numerous studies have highlighted the significance of METTL16 in various cellular functions and human diseases, though investigations have been relatively limited in past decades. In this work, we have summarized the current achievements in METTL16 studies related to human diseases, as illustrated in Figure 1. We anticipate that METTL16 will be a key area of focus in future studies on human diseases.

Figure 1 
               Schema of METTL16 in diseases.
Figure 1

Schema of METTL16 in diseases.

2 N6-methyladenosine modification

The m6A modification, formally known as N6-methyladenosine modification, represents a prominent type of RNA chemical modification, involving methylation at the N6 position of adenosine and standing as the most prevalent internal RNA modification detected within eukaryotic messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), and diverse other RNA species [2629]. The intricate orchestration of writers, erasers, and readers collaboratively governs the dynamic addition and removal of this modification [27]. Its influence extends across various realms of RNA biology, spanning splicing [30], stability [31], translation [32], and localization processes [33]. Furthermore, the m6A modification plays a pivotal role in a myriad of physiological processes, including embryonic development [34], cell differentiation [35], fertility [36], metabolism [37], and stress responses [38]. Crucially, the dysregulation of m6A modification emerges as a key player in a spectrum of human diseases, notably encompassing cancer [8], neurodegenerative disorders [39], and metabolic anomalies [40].

2.1 m6A writers, erasers, and readers

The m6A writers, erasers, and readers constitute the molecular composition of m6A RNA methylation regulator proteins [41]. These proteins collectively shape the m6A modification landscape on mRNAs and noncoding RNAs. Writers are responsible for inserting m6A marks, erasers remove them, and readers recognize and interpret the modification [42]. The primary writers category includes the METTL3–METTL14–WTAP methyltransferase complex, which orchestrates the addition of m6A modifications to specific adenosine residues in RNA molecules; while METTL3 and METTL14 act as the core catalytic units, WTAP enhances stability [6,18,40]. Erasers, represented by FTO and ALKBH5 demethylases, play a pivotal role in the reversible nature of m6A marks, influencing RNA stability and translation. FTO and ALKBH5 exhibit distinct substrate preferences and functions that influence m6A dynamics across different cellular contexts [43,44]. Readers, comprising diverse proteins like YTH domain-containing proteins (YTHDC1, YTHDC2, and YTHDF1-3) and other m6A-binding proteins (IGF2BP1-3 and HNRNPA2B1), interpret the m6A modification, triggering cellular responses that impact mRNA processing, splicing, and translation [4548]. These intricate interactions contribute to elaborate regulatory networks controlling gene expression and cell fate determination. The interplay among writers, erasers, and readers orchestrates a finely tuned regulatory network governing the dynamic m6A modification landscape. This collaboration integrates multiple layers of regulation, allowing cells to adapt to environmental cues and developmental signals. Maintaining the balanced function of m6A writers, erasers, and readers is crucial, as dysregulation has been linked to various diseases. Comprehensive reviews for detailed discussions on the role of m6A regulatory proteins in human diseases are already available in literature, as well as target therapy [42,4953]. For comprehensive information on current m6A methyltransferases, refer to Table 1.

Table 1

m6A writers, erasers, and readers

Types m6A regulator Full names
METTL3 Methyltransferase -like 3
WTAP Wilms tumor 1-associated protein
METTL14 Methyltransferase -like 14
VTRMA [KIAA1429] Vir-like ni6A methyltransferase associated
RBM15 RNA binding motif protein 15
RBM15B RNA binding motif protein 15B
METTL16 Methyltransferase-like 16
ZC3H13 Zine finger CCCH-type containing 13
METTL5 Methyltransferase-like 5
ZCCHC4 Zine finger CCHC-type containing 4
METTL4 Methyltransferase-like 4
MT-A70 S-adenosylmethionine -binding subunit of human mRNA
METTL7A Methyltransferase like 7A
METTL7B Methyltransferase like 7B
METTL11A Methyltransferase-like protein 11A
NSun2 Catalyses m6A modification
FTO Fat mass and obesity associated protein
ALKBH5 AlkB homolog 5
ALKBH3 AlkE homolog 3
YTHDF2 YTH N6-methyladenosine RNA binding protein 2
YTHDF1 YTH N6-methyladenosine RNA binding protein 1
elF3 Eukaryotic translation initiation factor 3 subunit A
HNRNFA2B1 Heterogeneous nuclear ribonucleoprotein A2/B1 nucleus
HNRNPG Heterogeneous nuclear ribonucleoprotein G
YTHDC1 YTH domain containing 1
YTHDF3 YTH N6-methyladenosine RNA binding protein 3
YTHDC2 YTH domain containing 2
IGF2BP1 Insulin-like growth factor 2 mRNA binding protein 1
IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2
IGF2BP3 Insulin-like growth factor 2 mRNA binding protein 3
FMRP Fragile X mental retardation protein
PRRC2A Proline rich coiled-coil 2 A
RBM33 RNA-binding motif protein 33
NKAP Mediates pri-miRNAs processing
RBM45 RNA-binding motif protein 45
HNRNPC Heterogeneous nuclear ribonucleoprotein C


More recently, another m6A methyltransferase, METTL16, has been identified. Although the function of this enzyme is not fully understood, its structure has been thoroughly studied. Human METTL16, belonging to class I SAM-MTases, possess a conserved SAM locus found in vertebrates and are made up of 562 amino acid residues [1416]. The construction primarily consists of an N-terminal MTD and two VCRs located at the C-terminus. Two disordered districts are found on either side of MTD and the two VCRs, as shown in Figure 2 [14,17,54]. As per current understanding, METTL16 is found in both the nucleus [42] and cytoplasm [43] and typically exists as a monomer [44,45]. However, upon binding with its substrate, MALAT1 triple-helix RNA, it forms a homodimer [16,54].

Figure 2 
               Sketch of human METTL16.
Figure 2

Sketch of human METTL16.

3.1 METTL16 in cancers

m6A modification and its associated regulated factors, including METTL3/METTL14, YTHDC, FTO, and ALKBH5, etc., have been widely researched for their roles in various types of cancer. However, the investigation of METTL16 in cancer is limited and there are only a few reports available to date.

3.2 Expression and prognostic significance of METTL16 in cancer

METTL16 has been identified as a potential gene involved in the initiation and progression of cancer. However, its expression varies across different tumor types and is associated with different outcomes. In some cases, it has been identified as highly expressed and associated with poor outcomes. For example, Wang et al. reported that METTL16 is highly expressed in gastric cancer and predicts worse survival in patients. The underlying molecular mechanism mainly involves METTL16 functioning as an m6A methyltransferase to promote cancer cell proliferation [55]. A clinical cohort study containing 66 hepatocellular carcinoma (HCC) tissues and 21 adjacent normal tissues determined that higher METTL16 expression group displayed a worse clinical outcome [56]. Additionally, bioinformatics analyses have shown that METTL16 is overexpressed in esophageal cancer [57], colorectal cancer (CRC) [58], and predicts poor survival in HCC, CRC, endocrine system tumors, glioma, melanoma, soft-tissue sarcomas, and breast cancer [22,5863]. While in other cases, there also have been reported that METTL16 is underexpressed in endometrial cancer [64], urothelial carcinoma [65], pancreatic ductal adenocarcinoma [66], and breast cancer [59]. In patients with pediatric neuroblastoma, Zhang et al. found that METTL16 could affect the overall survival and disease-free survival of patients [67]. In addition, in a RAS-related gene score of esophageal squamous cell carcinoma, METTL16 was found upregulated in the lower score group and predicted a better prognosis [68]. In a study to investigate m6A associated genes between patients with TP53 wild-type and mutation groups, METTL16 exhibited divergent expression between the groups [69].

METTL16 showed divergent expression in cancers, even in the same cancer, it has been found in different expressions in different studies, the underlying reasons should be further studied. Usually, METTL16 leads to bad prognosis; however, the effects on cancer prognosis can be modulated by other genes. These findings suggest that its role in cancer is complex and context-dependent. Recent studies uncovered that METTL16 can function as both m6A-dependent way or non-dependent way, both as a writer and a reader, both in cytoplasm or in nucleus, both regulate splice or translation, all of which showed a fantastic of METTL16. However, limited studies in specific cancers were conducted. Further research is needed to elucidate the molecular mechanisms underlying these effects and to explore the potential of METTL16 as a therapeutic target for cancer treatment.

3.3 METTL16 gene mutation in cancer

The identification of mutations in genes that diverged may play a significant role in understanding individual differences and recognizing diverse clinicopathological characteristics. Various studies have revealed that the METTL16 gene mutation is widespread in several types of cancer. In high microsatellite instability colorectal cancers, METTL16 contains frameshift mutations that are not present in normal tissues [70]. An analysis of METTL16 copy number variations (CNVs) using bioinformatics has shown that CNVs of this gene are common in cancers and can influence gene expression, leading to a worse prognosis. In more than 60% of sarcoma patients and 62.16% of HCC samples, METTL16 CNVs were present [63]. Furthermore, anti-tumor drugs have been associated with METTL16 mutation, and a study on methotrexate revealed that drug sensitivity to melanoma was linked to METTL16 mutations [62]. However, experimental validation and clinical data were lacking, indicating the need for further research in this area. Overall, the current study of METTL16 gene mutation showed the importance of gene mutations in cancers and the need for further research to develop effective treatment options for patients with cancer.

3.4 METTL16 and lncRNA

The lncRNA MALAT1 has an ENE+A structure and an METTL16 recognition sequence, allowing it to interact directly with METTL16 [24]. Studies have shown that MALAT1 can both facilitate and suppress cancer development and is common in various cancers [71,72]. An analysis of 89 pathways in 64 different cancers has revealed the presence of MALAT1 [73]. Additionally, MALAT1 can interact with microRNA and cancer drugs [74,75]. These studies highlights the significant associations of lncRNA MALAT1 or microRNA with METTL16, which has been shown to play a crucial role in regulating cellular signals and promoting cancer development. Another lncRNA, named lncRNA RAB11B-AS1, has recently been found to directly bind to METTL16, promoting cancer development in an m6A-dependent manner by decreasing lncRNA stability [76]. These findings suggest that METTL16 interacts with lncRNA and miRNA to regulate cellular signals and contribute to cancer development. However, further experiments are necessary to fully understand the role of METTL16 and RNAs in cancer.

3.5 METTL16 and DNA damage response (DDR)

DDR has been linked to the development of tumors. Studies have shown that during the early stages of DDR, there is a significant increase in N6-adenosine methylation in RNA following UV-micro-irradiation. In later stages, small RNAs, including snRNAs and snoRNAs, in the vicinity of DNA lesions were found to be methylated, and it was determined that METTL16 is the sole methyltransferase responsible for this process [77]. These findings suggest that METTL16 may play a critical role in cancer development related to DDR. However, the precise mechanism by which METTL16 contributes to DDR remains unknown.

3.6 Others

METTL16 has been reported to affect cell differentiation and protein translation. Studies have shown that the level of METTL16 is negatively associated with tumor cell differentiation and that the m6A level decreases with better differentiation [78]. METTL16 can regulate protein translation and aggravate cancer development by directly binding to TIC [22].

3.7 METTL16 in other diseases

Recent studies have shed light on the potential involvement of METTL16 in non-cancerous diseases across various human systems. In the digestive system, in HFD-induced mice and cell NAFLD models, the expression levels of METTL16 were substantially increased in the NAFLD model in vivo and in vitro. Furthermore, mechanism studies showed that METTL16 upregulated the expression level of lipogenic genes CIDEA in HepG2 cells [79]; otherwise, METTL16 also plays vital role in liver fibrosis [80]. In the respiratory system, research has shown that exposure to PM2.5 induces pulmonary vessel damage in an m6A-dependent manner through METTL16, providing new insights into the mechanisms of chronic obstructive pulmonary disease and cancer [81]. Additionally, in a mouse model of acute respiratory distress syndrome induced by LPS, researchers observed a gradual increase in m6A levels over 6 h, followed by a decrease. During this process, the METTL16 protein increased consecutively, while METTL16 mRNA decreased after LPS induction. The differences between METTL16 mRNA and protein expression warrant further investigation [82]. In the spinal system, studies have shown that the expression of METTL16 differs between human degenerative nucleus pulposus and control groups, and METTL16/MAT2A axis aggravates apoptosis of nucleus pulposus cells by regulating splicing, maturation, and degradation of MAT2A pre-mRNA [83]. In the endocrine system, a cross-sectional study for people of Middle Eastern descent revealed an association between METTL16 and diabetic nephropathy [84]. Additionally, in the reproductive system, research found that although the m6A level of pregnancy was elevated consistently, METTL16 was lower in patients with infertility and recrudescence abortion [85]. Finally, studies suggest that METTL16 may also play a role in cardiovascular and hematological systems, with low expression in immature RBCs of Hb CS thalassemia versus healthy controls [86] and contributing to mouse cardiomyocytes [87]. Moreover, METTL16 was identified to play a role in erythropoiesis through the repair of DDR [88]. Overall, these findings highlight the potential involvement of METTL16 in various non-cancerous diseases, emphasizing the wide roles of METTL16 in human disease, indicating the need for further research to elucidate the mechanisms of action and potential therapeutic applications.

4 Discussion and conclusion

METTL16 plays a vital role in cellular biogenesis and is associated with various human diseases. Studies have found that METTL16 knockdown can cause a significant decrease in the installation of m6A/A [17], and can even lead to embryonic lethality in mice [19]. While there is significant evidence that METTL16 is involved in both cancer and non-cancer diseases, the role that it plays is complex, with numerous paradoxes and contradictions. For example, METTL16 can be located in both the cytoplasm and nucleus, can function as both a writer and a reader, and can have both higher and lower levels of expression even in one disease of two studies. Additionally, it can exert its effects in multiple ways, such as directly binding to TIC or regulating target RNA splicing, stability, and more. It can function as both a promoter and as a suppressor of diseases, making it challenging to determine its overall effect. However, the studies of mechanisms or function of METTL16 in human diseases is absent, Moving forward, further research is needed to answer critical questions, such as how METTL16 influences human diseases, the mechanisms by which it exerts its effects, and whether its role varies depending on the cell type, disease, or individual.

Recognizing the pivotal role of METTL16 in disease contexts is of utmost importance. So, what is our next course of action? Recent research has unveiled a promising treatment approach for PDAC, particularly in cases where METTL16 expression is heightened, by combining PARPi with gemcitabine [89]. This breakthrough emphasizes the potential of targeting METTL16 for cancer therapy. Furthermore, it is crucial to evaluate METTL16 and its downstream RNA methylation targets as potential markers for disease diagnosis, prognosis, and monitoring of disease progression. Consequently, there is a pressing need to develop assays and diagnostic tools based on these findings. Simultaneously, we are actively exploring animal models and conducting clinical trials to deepen our comprehension. Additionally, we should embark on functional genomic studies aimed at uncovering the genes and pathways influenced by METTL16-mediated RNA methylation, shedding light on the broader implications of METTL16 in disease biology. Another avenue worth investigating is patient stratification, where we can assess METTL16-related mechanisms for their ability to categorize patients into subgroups with distinct disease outcomes or treatment responses. This approach holds significant promise for advancing personalized medicine initiatives.



copy number variations


colorectal cancer


element for nuclear expression with a downstream A-rich tract


hepatocellular carcinoma


red blood cell


Not applicable.

  1. Funding information: None.

  2. Author contributions: Mingliang Lu, Hui Zhang, and Mengqi Yin took responsibility for the integrity of the work as a whole, from inception to published article. Mingliang Lu, Hua Huang, and Gongfang Zhao gave support and indication. Hui Zhang wrote the article. All authors approved the final version of the manuscript.

  3. Conflict of interest: The authors declare that they have no competing interests.

  4. Data availability statement: The datasets used in the current study are available from the corresponding author or the first author on reasonable request.


[1] Pinto R, Vagbo CB, Jakobsson ME, Kim Y, Baltissen MP, O’Donohue MF, et al. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 2020;48(2):830–46.10.1093/nar/gkz1147Search in Google Scholar

[2] Golovina AY, Dzama MM, Osterman IA, Sergiev PV, Serebryakova MV, Bogdanov AA, et al. The last rRNA methyltransferase of E. coli revealed: the yhiR gene encodes adenine-N6 methyltransferase specific for modification of A2030 of 23S ribosomal RNA. RNA. 2012;18(9):1725–34.10.1261/rna.034207.112Search in Google Scholar

[3] Kowalak JA, Dalluge JJ, McCloskey JA, Stetter KO. The role of posttranscriptional modification in stabilization of transfer RNA from hyperthermophiles. Biochemistry. 1994;33(25):7869–76.10.1021/bi00191a014Search in Google Scholar

[4] Han X, Guo J, Fan Z. Interactions between m6A modification and miRNAs in malignant tumors. Cell Death Dis. 2021;12(6):598.10.1038/s41419-021-03868-5Search in Google Scholar

[5] Shima H, Matsumoto M, Ishigami Y, Ebina M, Muto A, Sato Y, et al. S-adenosylmethionine synthesis is regulated by selective N(6)-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep. 2017;21(12):3354–63.10.1016/j.celrep.2017.11.092Search in Google Scholar

[6] Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6(1):74.10.1038/s41392-020-00450-xSearch in Google Scholar

[7] Chen X, Wang J, Tahir M, Zhang F, Ran Y, Liu Z, et al. Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases. Cell Biosci. 2021;11(1):147.10.1186/s13578-021-00661-xSearch in Google Scholar

[8] Zhou Y, Yang J, Tian Z, Zeng J, Shen W. Research progress concerning m(6)A methylation and cancer. Oncol Lett. 2021;22(5):775.10.3892/ol.2021.13036Search in Google Scholar

[9] Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552(7683):126–31.10.1038/nature24678Search in Google Scholar

[10] Zhang L, Luo X, Qiao S. METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma. Br J Cancer. 2022;127(1):30–42.10.1038/s41416-022-01757-ySearch in Google Scholar

[11] Wang J. Trapping m6A proteins for splicing regulation. Nat Cell Biol. 2021;23(8):811.10.1038/s41556-021-00737-3Search in Google Scholar

[12] Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 2016;62(3):335–45.10.1016/j.molcel.2016.03.021Search in Google Scholar

[13] Yang S, Wei J, Cui YH, Park G, Shah P, Deng Y, et al. m(6)A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019;10(1):2782.10.1038/s41467-019-10669-0Search in Google Scholar

[14] Ruszkowska A. METTL16, methyltransferase-like protein 16: current insights into structure and function. Int J Mol Sci. 2021;22(4):2176.10.3390/ijms22042176Search in Google Scholar

[15] Stixova L, Komurkova D, Svobodova Kovarikova A, Fagherazzi P, Bartova E. Localization of METTL16 at the nuclear periphery and the nucleolus is cell cycle-specific and METTL16 interacts with several nucleolar proteins. Life (Basel). 2021;11(7):669.10.3390/life11070669Search in Google Scholar

[16] Ruszkowska A, Ruszkowski M, Dauter Z, Brown JA. Structural insights into the RNA methyltransferase domain of METTL16. Sci Rep. 2018;8(1):5311.10.1038/s41598-018-23608-8Search in Google Scholar

[17] Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, et al. The U6 snRNA m(6)A methyltransferase METTL16 regulates sam synthetase intron retention. Cell. 2017;169(5):824–35.e814.10.1016/j.cell.2017.05.003Search in Google Scholar

[18] Oerum S, Meynier V, Catala M, Tisne C. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021;49(13):7239–55.Search in Google Scholar

[19] Mendel M, Chen KM, Homolka D, Gos P, Pandey RR, McCarthy AA, et al. Methylation of structured RNA by the m(6)A writer METTL16 is essential for mouse embryonic development. Mol Cell. 2018;71(6):986–1000.e1011.10.1016/j.molcel.2018.08.004Search in Google Scholar

[20] Doxtader KA, Wang P, Scarborough AM, Seo D, Conrad NK, Nam Y. Structural basis for regulation of METTL16, an S-adenosylmethionine homeostasis factor. Mol Cell. 2018;71(6):1001–11.e1004.10.1016/j.molcel.2018.07.025Search in Google Scholar

[21] Watabe E, Togo-Ohno M, Ishigami Y, Wani S, Hirota K, Kimura-Asami M, et al. m(6)A-mediated alternative splicing coupled with nonsense-mediated mRNA decay regulates SAM synthetase homeostasis. EMBO J. 2021;40(14):e106434.10.15252/embj.2020106434Search in Google Scholar

[22] Su R, Dong L, Li Y, Gao M, He PC, Liu W, et al. METTL16 exerts an m(6)A-independent function to facilitate translation and tumorigenesis. Nat Cell Biol. 2022;24(2):205–16.10.1038/s41556-021-00835-2Search in Google Scholar PubMed PubMed Central

[23] Warda AS, Kretschmer J, Hackert P, Lenz C, Urlaub H, Höbartner C, et al. Human METTL16 is a N(6)-methyladenosine (m(6)A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Rep. 2017;18(11):2004–14.10.15252/embr.201744940Search in Google Scholar PubMed PubMed Central

[24] Brown JA, Kinzig CG, DeGregorio SJ, Steitz JA. Methyltransferase-like protein 16 binds the 3’-terminal triple helix of MALAT1 long noncoding RNA. Proc Natl Acad Sci U S A. 2016;113(49):14013–8.10.1073/pnas.1614759113Search in Google Scholar PubMed PubMed Central

[25] Covelo-Molares H, Obrdlik A, Postulkova I, Dohnalkova M, Gregorova P, Ganji R, et al. The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features. Nucleic Acids Res. 2021;49(19):10895–910.10.1093/nar/gkab900Search in Google Scholar PubMed PubMed Central

[26] Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201–6.10.1038/nature11112Search in Google Scholar PubMed

[27] Wang S, Lv W, Li T, Zhang S, Wang H, Li X, et al. Dynamic regulation and functions of mRNA m6A modification. Cancer Cell Int. 2022;22(1):48.10.1186/s12935-022-02452-xSearch in Google Scholar PubMed PubMed Central

[28] Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z, et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial–mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 2019;18(1):142.10.1186/s12943-019-1065-4Search in Google Scholar PubMed PubMed Central

[29] Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37(3):270–88.10.1016/j.ccell.2020.02.004Search in Google Scholar PubMed PubMed Central

[30] Bartosovic M, Molares HC, Gregorova P, Hrossova D, Kudla G, Vanacova S. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3’-end processing. Nucleic Acids Res. 2017;45(19):11356–70.10.1093/nar/gkx778Search in Google Scholar PubMed PubMed Central

[31] Liu Z, Chen Y, Wang L, Ji S. ALKBH5 promotes the proliferation of glioma cells via enhancing the mRNA stability of G6PD. Neurochem Res. 2021;46(11):3003–11.10.1007/s11064-021-03408-9Search in Google Scholar PubMed

[32] Jain S, Koziej L, Poulis P, Kaczmarczyk I, Gaik M, Rawski M, et al. Modulation of translational decoding by m(6)A modification of mRNA. Nat Commun. 2023;14(1):4784.10.1038/s41467-023-40422-7Search in Google Scholar PubMed PubMed Central

[33] Loedige I, Baranovskii A, Mendonsa S, Dantsuji S, Popitsch N, Breimann L, et al. mRNA stability and m(6)A are major determinants of subcellular mRNA localization in neurons. Mol Cell. 2023;83(15):2709–25.e2710.10.1016/j.molcel.2023.06.021Search in Google Scholar PubMed PubMed Central

[34] Liu H, Zheng J, Liao A. The regulation and potential roles of m6A modifications in early embryonic development and immune tolerance at the maternal–fetal interface. Front Immunol. 2022;13:988130.10.3389/fimmu.2022.988130Search in Google Scholar PubMed PubMed Central

[35] Huang M, Xu S, Liu L, Zhang M, Guo J, Yuan Y, et al. m6A methylation regulates osteoblastic differentiation and bone remodeling. Front Cell Dev Biol. 2021;9:783322.10.3389/fcell.2021.783322Search in Google Scholar PubMed PubMed Central

[36] Wan S, Sun Y, Zong J, Meng W, Yan J, Chen K, et al. METTL3-dependent m(6)A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling. Cell Death Dis. 2023;14(6):349.10.1038/s41419-023-05866-1Search in Google Scholar PubMed PubMed Central

[37] Zhong X, Yu J, Frazier K, Weng X, Li Y, Cham CM, et al. Circadian clock regulation of hepatic lipid metabolism by modulation of m(6)A mRNA methylation. Cell Rep. 2018;25(7):1816–28.e1814.10.1016/j.celrep.2018.10.068Search in Google Scholar PubMed PubMed Central

[38] Xu Z, Qiu P, Jiang Y, Hu J, Wu Z, Lei J, et al. m6A modification mediates endothelial cell responses to oxidative stress in vascular aging induced by low fluid shear stress. Oxid Med Cell Longev. 2023;2023:8134027.10.1155/2023/8134027Search in Google Scholar PubMed PubMed Central

[39] Han M, Liu Z, Xu Y, Liu X, Wang D, Li F, et al. Abnormality of m6A mRNA methylation is involved in Alzheimer’s disease. Front Neurosci. 2020;14:98.10.3389/fnins.2020.00098Search in Google Scholar PubMed PubMed Central

[40] Zhang Y, Chen W, Zheng X, Guo Y, Cao J, Zhang Y, et al. Regulatory role and mechanism of m(6)A RNA modification in human metabolic diseases. Mol Ther Oncolytics. 2021;22:52–63.10.1016/j.omto.2021.05.003Search in Google Scholar PubMed PubMed Central

[41] Zhao Y, Shi Y, Shen H, Xie W. m(6)A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol. 2020;13(1):35.10.1186/s13045-020-00872-8Search in Google Scholar PubMed PubMed Central

[42] Flamand MN, Tegowski M, Meyer KD. The proteins of mRNA modification: writers, readers, and erasers. Annu Rev Biochem. 2023;92:145–73.10.1146/annurev-biochem-052521-035330Search in Google Scholar PubMed PubMed Central

[43] Zhou LL, Xu H, Huang Y, Yang CG. Targeting the RNA demethylase FTO for cancer therapy. RSC Chem Biol. 2021;2(5):1352–69.10.1039/D1CB00075FSearch in Google Scholar PubMed PubMed Central

[44] Kaur S, Tam NY, McDonough MA, Schofield CJ, Aik WS. Mechanisms of substrate recognition and N6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes. Nucleic Acids Res. 2022;50(7):4148–60.10.1093/nar/gkac195Search in Google Scholar PubMed PubMed Central

[45] Zhou Z, Lv J, Yu H, Han J, Yang X, Feng D, et al. Mechanism of RNA modification N6-methyladenosine in human cancer. Mol Cancer. 2020;19(1):104.10.1186/s12943-020-01216-3Search in Google Scholar PubMed PubMed Central

[46] Qiao Y, Sun Q, Chen X, He L, Wang D, Su R, et al. Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export. Elife. 2023;12:e82703.10.7554/eLife.82703Search in Google Scholar PubMed PubMed Central

[47] Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020;48(7):3816–31.10.1093/nar/gkaa048Search in Google Scholar PubMed PubMed Central

[48] Fang Z, Mei W, Qu C, Lu J, Shang L, Cao F, et al. Role of m6A writers, erasers and readers in cancer. Exp Hematol Oncol. 2022;11(1):45.10.1186/s40164-022-00298-7Search in Google Scholar PubMed PubMed Central

[49] Deng LJ, Deng WQ, Fan SR, Chen MF, Qi M, Lyu WY, et al. m6A modification: recent advances, anticancer targeted drug discovery and beyond. Mol Cancer. 2022;21(1):52.10.1186/s12943-022-01510-2Search in Google Scholar PubMed PubMed Central

[50] Shen LT, Che LR, He Z, Lu Q, Chen DF, Qin ZY, et al. Aberrant RNA m(6)A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities. Cell Death Dis. 2023;14(4):236.10.1038/s41419-023-05736-wSearch in Google Scholar PubMed PubMed Central

[51] Petri BJ, Klinge CM. m6A readers, writers, erasers, and the m6A epitranscriptome in breast cancer. J Mol Endocrinol. 2023;70(2):e220110.10.1530/JME-22-0110Search in Google Scholar PubMed PubMed Central

[52] Zhu X, Zhou C, Zhao S, Zheng Z. Role of m6A methylation in retinal diseases. Exp Eye Res. 2023;231:109489.10.1016/j.exer.2023.109489Search in Google Scholar PubMed

[53] Qi YN, Liu Z, Hong LL, Li P, Ling ZQ. Methyltransferase-like proteins in cancer biology and potential therapeutic targeting. J Hematol Oncol. 2023;16(1):89.10.1186/s13045-023-01477-7Search in Google Scholar PubMed PubMed Central

[54] Oerum S, Meynier V, Catala M, Tisné C. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021;49(13):7239–55.10.1093/nar/gkab378Search in Google Scholar PubMed PubMed Central

[55] Wang XK, Zhang YW, Wang CM, Li B, Zhang TZ, Zhou WJ, et al. METTL16 promotes cell proliferation by up-regulating cyclin D1 expression in gastric cancer. J Cell Mol Med. 2021;25(14):6602–17.10.1111/jcmm.16664Search in Google Scholar PubMed PubMed Central

[56] Wang P, Wang X, Zheng L, Zhuang C. Gene signatures and prognostic values of m6A regulators in hepatocellular carcinoma. Front Genet. 2020;11:540186.10.3389/fgene.2020.540186Search in Google Scholar PubMed PubMed Central

[57] Zhao H, Xu Y, Xie Y, Zhang L, Gao M, Li S, et al. m6A regulators is differently expressed and correlated with immune response of esophageal cancer. Front Cell Dev Biol. 2021;9:650023.10.3389/fcell.2021.650023Search in Google Scholar PubMed PubMed Central

[58] Liu X, Liu L, Dong Z, Li J, Yu Y, Chen X, et al. Expression patterns and prognostic value of m(6)A-related genes in colorectal cancer. Am J Transl Res. 2019;11(7):3972–91.Search in Google Scholar

[59] Zhang B, Gu Y, Jiang G. Expression and prognostic characteristics of m(6)A RNA methylation regulators in breast cancer. Front Genet. 2020;11:604597.10.3389/fgene.2020.604597Search in Google Scholar PubMed PubMed Central

[60] Cong P, Wu T, Huang X, Liang H, Gao X, Tian L, et al. Identification of the role and clinical prognostic value of target genes of m6A RNA methylation regulators in glioma. Front Cell Dev Biol. 2021;9:709022.10.3389/fcell.2021.709022Search in Google Scholar PubMed PubMed Central

[61] Li K, Luo H, Luo H, Zhu X. Clinical and prognostic pan-cancer analysis of m6A RNA methylation regulators in four types of endocrine system tumors. Aging (Albany NY). 2020;12(23):23931–44.10.18632/aging.104064Search in Google Scholar PubMed PubMed Central

[62] Liu J, Zhou Z, Ma L, Li C, Lin Y, Yu T, et al. Effects of RNA methylation N6-methyladenosine regulators on malignant progression and prognosis of melanoma. Cancer Cell Int. 2021;21(1):453.10.1186/s12935-021-02163-9Search in Google Scholar PubMed PubMed Central

[63] Hou M, Guo X, Chen Y, Cong L, Pan C, Prognostic A. Molecular signature of N⁶-methyladenosine methylation regulators for soft-tissue sarcoma from the cancer genome atlas database. Med Sci Monit. 2020;26:e928400.10.12659/MSM.928400Search in Google Scholar

[64] Zhang Y, Yang Y. Effects of m6A RNA methylation regulators on endometrial cancer. J Clin Lab Anal. 2021;35(9):e23942.10.1002/jcla.23942Search in Google Scholar

[65] Zheng B, Wang J, Zhao G, Chen X, Yao Z, Niu Z, et al. A new m6A methylation-related gene signature for prognostic value in patient with urothelial carcinoma of the bladder. Biosci Rep. 2021;41(4):BSR2020445.10.1042/BSR20204456Search in Google Scholar

[66] Lu L, Zheng D, Qu J, Zhuang Y, Peng J, Lan S, et al. METTL16 predicts a favorable outcome and primes antitumor immunity in pancreatic ductal adenocarcinoma. Front Cell Dev Biol. 2022;10:759020.10.3389/fcell.2022.759020Search in Google Scholar

[67] Zhang C, Ding Z, Luo H. The prognostic role of m6A-related genes in paediatric neuroblastoma patients. Comput Math Methods Med. 2022;2022:8354932.10.1155/2022/8354932Search in Google Scholar

[68] Yang HS, Liu W, Zheng SY, Cai HY, Luo HH, Feng YF, et al. Ras-related signature improves prognostic capacity in oesophageal squamous cell carcinoma. Front Genet. 2022;13:822966.10.3389/fgene.2022.822966Search in Google Scholar

[69] Zhao Z, Wan J, Guo M, Wang Y, Yang Z, Zhou F, et al. Expression and prognostic significance of m6A-related genes in TP53-mutant non-small-cell lung cancer. J Clin Lab Anal. 2022;36(1):e24118.10.1002/jcla.24118Search in Google Scholar

[70] Yeon SY, Jo YS, Choi EJ, Kim MS, Yoo NJ, Lee SH. Frameshift mutations in repeat sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 genes in colon cancers. Pathol Oncol Res. 2018;24(3):617–22.10.1007/s12253-017-0287-2Search in Google Scholar

[71] Kim J, Piao HL, Kim BJ, Yao F, Han Z, Wang Y, et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet. 2018;50(12):1705–15.10.1038/s41588-018-0252-3Search in Google Scholar

[72] Sun Z, Ou C, Liu J, Chen C, Zhou Q, Yang S, et al. YAP1-induced MALAT1 promotes epithelial–mesenchymal transition and angiogenesis by sponging miR-126-5p in colorectal cancer. Oncogene. 2019;38(14):2627–44.10.1038/s41388-018-0628-ySearch in Google Scholar

[73] Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321–37.e310.Search in Google Scholar

[74] Bai L, Wang A, Zhang Y, Xu X, Zhang X. Knockdown of MALAT1 enhances chemosensitivity of ovarian cancer cells to cisplatin through inhibiting the Notch1 signaling pathway. Exp Cell Res. 2018;366(2):161–71.10.1016/j.yexcr.2018.03.014Search in Google Scholar PubMed

[75] Zheng L, Zhang Y, Fu Y, Gong H, Guo J, Wu K, et al. Long non-coding RNA MALAT1 regulates BLCAP mRNA expression through binding to miR-339-5p and promotes poor prognosis in breast cancer. Biosci Rep. 2019;39(2):BSR20181284.10.1042/BSR20181284Search in Google Scholar PubMed PubMed Central

[76] Dai YZ, Liu YD, Li J, Chen MT, Huang M, Wang F, et al. METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m(6)A-dependent manner. Cell Mol Biol Lett. 2022;27(1):41.10.1186/s11658-022-00342-8Search in Google Scholar PubMed PubMed Central

[77] Svobodová Kovaříková A, Stixová L, Kovařík A, Komůrková D, Legartová S, Fagherazzi P, et al. N(6)-adenosine methylation in RNA and a reduced m(3)G/TMG level in non-coding RNAs appear at microirradiation-induced DNA lesions. Cells. 2020;9(2):360.10.3390/cells9020360Search in Google Scholar PubMed PubMed Central

[78] Wang S, Fan X, Zhu J, Xu D, Li R, Chen R, et al. The differentiation of colorectal cancer is closely relevant to m6A modification. Biochem Biophys Res Commun. 2021;546:65–73.10.1016/j.bbrc.2021.02.001Search in Google Scholar PubMed

[79] Tang J, Zhao X, Wei W, Liu W, Fan H, Liu XP, et al. METTL16-mediated translation of CIDEA promotes non-alcoholic fatty liver disease progression via m6A-dependent manner. PeerJ. 2022;10:e14379.10.7717/peerj.14379Search in Google Scholar PubMed PubMed Central

[80] Gao H, Wang X, Ma H, Lin S, Zhang D, Wu W, et al. METTL16 regulates m(6)A methylation on chronic hepatitis B associated gene HLA-DPB1 involved in liver fibrosis. Front Genet. 2022;13:996245.10.3389/fgene.2022.996245Search in Google Scholar PubMed PubMed Central

[81] Guo X, Lin Y, Lin Y, Zhong Y, Yu H, Huang Y, et al. PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification. Environ Pollut. 2022;303:119115.10.1016/j.envpol.2022.119115Search in Google Scholar PubMed

[82] Fei L, Sun G, Sun J, Wu D. The effect of N6-methyladenosine (m6A) factors on the development of acute respiratory distress syndrome in the mouse model. Bioengineered. 2022;13(3):7622–34.10.1080/21655979.2022.2049473Search in Google Scholar PubMed PubMed Central

[83] Chen PB, Shi GX, Liu T, Li B, Jiang SD, Zheng XF, et al. Oxidative stress aggravates apoptosis of nucleus pulposus cells through m(6)A modification of MAT2A pre-mRNA by METTL16. Oxid Med Cell Longev. 2022;2022:4036274.10.1155/2022/4036274Search in Google Scholar PubMed PubMed Central

[84] Mohamed SA, Fernadez-Tajes J, Franks PW, Bennet L. GWAS in people of Middle Eastern descent reveals a locus protective of kidney function – a cross-sectional study. BMC Med. 2022;20(1):76.10.1186/s12916-022-02267-7Search in Google Scholar PubMed PubMed Central

[85] Zhao S, Lu J, Chen Y, Wang Z, Cao J, Dong Y. Exploration of the potential roles of m6A regulators in the uterus in pregnancy and infertility. J Reprod Immunol. 2021;146:103341.10.1016/j.jri.2021.103341Search in Google Scholar PubMed

[86] Ruan H, Yang F, Deng L, Yang D, Zhang X, Li X, et al. Human m(6)A-mRNA and lncRNA epitranscriptomic microarray reveal function of RNA methylation in hemoglobin H-constant spring disease. Sci Rep. 2021;11(1):20478.10.1038/s41598-021-99867-9Search in Google Scholar PubMed PubMed Central

[87] Arcidiacono OA, Krejčí J, Bártová E. The distinct function and localization of METTL3/METTL14 and METTL16 enzymes in cardiomyocytes. Int J Mol Sci. 2020;21:21.10.3390/ijms21218139Search in Google Scholar PubMed PubMed Central

[88] Yoshinaga M, Han K, Morgens DW, Horii T, Kobayashi R, Tsuruyama T, et al. The N(6)-methyladenosine methyltransferase METTL16 enables erythropoiesis through safeguarding genome integrity. Nat Commun. 2022;13(1):6435.10.1038/s41467-022-34078-ySearch in Google Scholar PubMed PubMed Central

[89] Zeng X, Zhao F, Cui G, Zhang Y, Deshpande RA, Chen Y, et al. METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Nat Cancer. 2022;3(9):1088–104.10.1038/s43018-022-00429-3Search in Google Scholar PubMed

Received: 2023-07-03
Revised: 2023-10-09
Accepted: 2023-10-27
Published Online: 2023-11-30

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Downloaded on 28.2.2024 from
Scroll to top button