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Open Access 01.12.2021 | Review

Recent advances of m⁶A methylation modification in esophageal squamous cell carcinoma

verfasst von: Xiaoqing Zhang, Ning Lu, Li Wang, Yixuan Wang, Minna Li, Ying Zhou, Manli Cui, Mingxin Zhang, Lingmin Zhang

Erschienen in: Cancer Cell International | Ausgabe 1/2021

Abstract

In recent years, with the development of RNA sequencing technology and bioinformatics methods, the epigenetic modification of RNA based on N⁶-methyladenosine (m⁶A) has gradually become a research hotspot in the field of bioscience. m⁶A is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs). m⁶A methylation modification can dynamically and reversibly regulate RNA transport, localization, translation and degradation through the interaction of methyltransferase, demethylase and reading protein. m⁶A methylation can regulate the expression of proto-oncogenes and tumor suppressor genes at the epigenetic modification level to affect tumor occurrence and metastasis. The morbidity and mortality of esophageal cancer (EC) are still high worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common tissue subtype of EC. This article reviews the related concepts, biological functions and recent advances of m⁶A methylation in ESCC, and looks forward to the prospect of m⁶A methylation as a new diagnostic biomarker and potential therapeutic target for ESCC.

Co-first author: Xiaoqing Zhang, Ning Lu, and Li Wang contributed equally to this work

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m⁶A

N6-methyladenosine

mRNAs

Messenger RNAs

Esophageal cancer

ESCC

Esophageal squamous cell carcinoma

METTL3

Methyltransferase like 3

WTAP

Wilms' tumor 1 associated protein

VIRMA

Virilizer like m⁶A methyltransferase

RBM15

RNA binding motif protein 15

ZC3H13

Zinc finger CCCH domain-containing protein 13

CBLL1

Casitas B-lineage lymphoma-transforming sequence-like protein 1

ALKBH5

AlkB homolog 5

FTO

Fat mass and obesity associated

YTHDF

YT521-B homology domain family

YTHDC

YT521-B homology domain containing

HNRNP

Heterogeneous nuclear ribonucleoprotein binding protein

IGF2BP2

Insulin like growth factor 2 mRNA binding protein 2

eIF3

Eukaryotic translation initiation factor

ELAVL1

ELAV like RNA binding protein 1

TCGA

The cancer genome atlas

GEPIA

Gene Expression Profiling Interactive Analysis

KEGG

Kyoto Encyclopedia of Genes and Genomes

SiRNA

Small interfer RNA

MMP13

Upregulating matrix metallopeptidase 13

ACLY

ATP citrate lyase

ACC1

Aminocyclopropane- 1-carboxylate

Overall survival

Introduction

Esophageal cancer (EC) is one of the most invasive malignant tumors of digestive tract in the world, and its morbidity and mortality are still high in China [1]. 90% of the histopathological types of esophageal cancer are esophageal squamous cell carcinoma (ESCC) [2]. EC is caused by a variety of causes, among which genetic and epigenetic modifications play a key role in the occurrence and development of ESCC [3, 4]. In recent years, although surgical resection, combined radiotherapy and chemotherapy have improved the prognosis of patients with ESCC, the 5-year overall survival rate is still very low [5], between 20 and 30% [6]. Therefore, there is an urgent need to find new diagnostic biomarkers and potential therapeutic targets for ESCC patients.

In recent years, with the continuous development of tumor epigenetics, N6-methyladenine (m⁶A) has not only initiated a new era of post-transcriptional gene regulation in eukaryotes, but also rapidly become a research hotspot in the field of RNA methylation modification. As a reversible RNA methylation modification, m⁶A methylation is dynamically regulated by a variety of regulatory factors [7]. The imbalance of m⁶A methylation regulators changes the biological functions of cell proliferation, migration and invasion, and finally leads to the occurrence and development of tumor.

This article reviews the related concepts and biological functions of m⁶A methylation and the research progress in ESCC. In addition, it also emphasizes the prospect of m⁶A methylation as a new diagnostic biomarker and potential therapeutic target for ESCC.

m⁶A refers to the methylation at the N6 position of adenosine, which is mainly concentrated in the 3'untranslated region near the mRNA Terminator. m⁶A modification mainly occurs in the RRm⁶ACH sequence [8]. As one of the most common and abundant internal modifications in mammals and eukaryotes [9], m⁶A RNA modification involves almost all aspects of RNA metabolism [10]. Its regulation process is mainly dynamically and reversibly regulated by a variety of regulatory factors. The methylated proteins involved in m⁶A methylation are mainly methyltransferases, demethylases and RNA binding proteins [11‐13]. They can add, remove or give priority to recognize m⁶A sites, which play a key regulatory role in the expression of the whole genome and have a great impact on normal physiological function or pathological status [14].

m⁶A is involved in many cellular RNA processes, including transcription, splicing, nuclear transport, translation and degradation [12, 15]. By affecting the stability and half-life of mRNA, m⁶A regulates gene expression and regulates important biological functions such as mammalian reproductive function, circadian rhythm, adipogenesis and human lifespan [16]. Its interference may affect gene table regulation and cell biological function [17], and indirectly affect the stability and half-life of mRNA, leading to tumors and many diseases. The basic mechanism of m⁶A methylation in RNA is shown in Fig. 1.

m⁶A modified writing gene (writers)

The written genes are various methyltransferases that promote m⁶A RNA methylation modification. At present, the components identified by m⁶A methyltransferase include methyltransferase like 3 (METTL3), METTL14, Wilms' tumor 1 associated protein (WTAP), and Virilizer like m⁶A methyltransferase associated protein (VIRMA/KIAA1429), RNA binding motif protein 15 (RBM15), zinc finger CCCH domain-containing protein 13 (ZC3H13), Casitas B-lineage lymphoma-transforming sequence-like protein 1, CBLL1/HAKAI).

Methyltransferase mainly forms stable complexes through core proteins such as METTL3, METTL14 and WTAP. m⁶A methylation occurs on the bases of mRNA [18], in which METTL3 is a subunit with catalytic activity, METTL14 is responsible for recognizing the substrate, WATP is mainly responsible for assisting METTL3 and METTL14 to target to nuclear spots, and WTAP has independent methylation sites, which can make some m⁶A sites specific methylation. VIRMA/KIAA1429, another component of methyltransferase complex, is a protein involved in alternative splicing and interacts with WTAP.

m⁶A modified eraser gene (erasers)

The erase gene can remove the m⁶A modification in the RNA molecule by encoding m⁶A demethylase, which is the key to the reversible process of m⁶A modification [19]. m⁶A demethylase has been identified as AlkB homolog 5 (ALKBH5) [20] and fat mass and obesity associated (FTO) [21]. Although they have similar functions, but the action process is different.

ALKBH5 can catalyze the m⁶A modification demethylation of RNA in vitro [20], which can significantly affect the output of mRNA and RNA metabolism as well as the assembly of mRNA processing factors in nuclear spots. FTO has the function of demethylation of m⁶A on single-stranded DNA and RNA, and they are highly expressed in fat, brain and hypothalamus [22], which is vital to metabolism.

m⁶A modified reading protein (readers)

The protein that selectively binds to the post-transcriptional product of m⁶A is called m⁶A reading protein. At present, the research on m⁶A modified reading protein is mainly focused on the YT521-B homology domain family (YTHDF), YT521-B homology domain containing (YTHDC), heterogeneous nuclear ribonucleoprotein binding protein (HNRNP), and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2), eukaryotic translation initiation factor (eIF3) and ELAV like RNA binding protein 1 (ELAVL1/HuR).

YTHDC1 may affect the splicing of mRNA and its output from the nucleus [15]. YTHDF2, YTHDF3 and YTHDC2, such as YTHDF2, which promote the degradation of mRNA, can selectively bind to methylated mRNA, participate in the storage and degradation of mRNA, affect the decay process of mRNA, and may have a positive effect on human lifespan [23]. It is IGF2BP1/2/3 that maintains the stability of mRNA [24], and it is YTHDF1, YTHDF3, YTHDC2 and IGF2BP1/2/3, that promote the translation of target mRNA. Among them, YTHDF3 can assist YTHDF1 to jointly promote the translation of related mRNA [25].

The role and significance of m⁶A methylation in ESCC

Studies have shown that m⁶A modified mRNA is maladjusted in many cancers, and its role in cancer has been gradually confirmed in vivo and in vitro, not only non-coding "writing genes", "erasing genes" and "reading genes", but also other protein factors, including oncogenes, transcription factors and signal transduction factors. the overexpression or consumption of these m⁶A-related factors may change the m⁶A modification in the tumor and interfere with the progression of cancer. The role of m⁶A regulatory factor in ESCC is shown in Table 1. Therefore, to clarify the molecular mechanism of these changes of m⁶A modified RNA and identifying the abnormal expression of m⁶A regulatory factors in clinical biopsy specimens. It is of great significance for early diagnosis of tumors, prediction of tumor prognosis and provision of new approaches of tumor treatment.

Table 1

The role of m⁶A regulator in ESCC

m⁶A modified type	m⁶A modification related protein	Expression	Occurrence and development of tumor	Study model	Biological Function	Ref.
m⁶A writers	METTL3	Upregulated	Promote	In vivo: human	The malignant phenotype of ESCC cells was significantly inhibited by down-regulating PI3K/AKT signal pathway	[30, 31]
m⁶A erasers	ALKBH5	Downregulated	Inhibition	–	There is a positive feedback regulation node between miR-193a-3p and ALKBH5 in esophageal cancer cells	[26]
m⁶A erasers	FTO	Upregulated	Promote	In vitro: KYSE150, Eca-109, TE-1	Up-regulation of MMP13 promotes cell proliferation and migration in esophageal squamous cell carcinoma	[32]
m⁶A readers	YTHDC2	Downregulated	Promote	In vitro: HET-1A,TE-9, Eca-109,KYSE150, EC9706	rs2416282 participates in the risk of esophageal cancer by regulating the expression of YTHDC2	[31]
	HNRNPA2B1	Upregulated	Promote	In vitro: HEEpiC, ECA109, TE10	Promoting the progress of ESCC by up-regulating the expression of fatty acid synthase ACLY and ACC1	[33]
	HNRNPC	Upregulated	Promote	-	HNRNPC may be the promoter of ESCA carcinogenesis	[34]

ALKBH5

Previous studies [26] have found that, the expression of ALKBH5 in EC tissue decreased. Functional analysis showed that ALKBH5 could inhibit the proliferation, migration and invasion of EC cells. However, a recent study found that ALKBH5 promotes the proliferation and migration of ESCC [27]. These results contradict previous findings. The reason may be that this study did not compare the differential expression patterns between ESCC and normal esophageal tissue, but only detected the expression of ALKBH5 in ESCC. The results of the cancer genome atlas (TCGA) database through Gene Expression Profiling Interactive Analysis (GEPIA) online tool show that the overall survival time of patients with high expression of ALKBH5 is longer than that of patients with low expression, indicating that ALKBH5 plays a tumor inhibitory role in EC [28]. ALKBH5 regulates cell proliferation, migration, invasion, tumor progression, metastasis, tumorigenesis and chemotherapy resistance might by regulating m⁶A methylation.

YTHDC2

Yang et al. [29] through the study of the database, it was observed that the expression of YTHDC2 was downregulated in esophageal cancer. In the proliferation experiment, it was found that the low expression of YTHDC2 significantly promoted the growth of cells, suggesting that YTHDC2 may play a role as a tumor suppressor in ESCC. In the further enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, it was observed that several pathological pathways related to ESCC, including p53 signal pathway, NF-kappaB signal pathway and JAK-STAT signal pathway, were significantly rich in downregulated genes, thus promoting the proliferation of ESCC cells.

METTL3

METTL3 is the core catalytic component of methyltransferase complex. Xia et al. [30] detected the expression of METTL3 in 207 patients with ESCC. The results of open data set and immunohistochemistry showed that the expression of METTL3 in tumor tissues was up-regulated compared with normal tissues adjacent to cancer, and the higher the expression level of METTL3 was, the worse the survival time was. In addition, it was also found that the expression level of METTL3 was an independent predictor of disease-free survival and overall survival in patients with ESCC. Another study [31] showed that small interfer RNA (siRNA) gene knockout of METTL3 inhibited the survival, colony formation, migration and invasion of EC cells, induced apoptosis, and significantly inhibited the malignant phenotype of ESCC cells by down-regulating PI3K/AKT signal pathway. In conclusion, METTL3 is a good predictor of ESCC and can be used as a potential biomarker for the prognosis of ESCC.

FTO

A study [32] through immunohistochemistry and data mining of 80 pairs of ESCC tissues, it was found that the expression of FTO in ESCC tissues was higher than that in adjacent normal tissues. The survival curve shows that the high expression of FTO has the trend of poor prognosis. A large number of evidence in the study confirmed that the downregulated expression of FTO can significantly inhibit the proliferation and migration of ESCC. In addition, FTO promotes cell proliferation and migration in ESCC by upregulating matrix metallopeptidase 13 (MMP13). Therefore, FTO acts as a tumor promoter in the progression of ESCC.

HNRNPA2B1

Guo et al. [33] found that the expression of m⁶A and its regulatory factor HNRNPA2B1 was significantly increased in ESCC tissues, and the high expression of HNRNPA2B1 was positively correlated with tumor diameter and lymph node metastasis of ESCC. In addition, functional studies have shown that HNRNPA2B1 gene knockout inhibits the proliferation, migration and invasion of ESCC. In terms of mechanism, HNRNPA2B1 promotes the progress of ESCC by up-regulating the expression of fatty acid synthase ATP citrate lyase (ACLY) and aminocyclopropane- 1-carboxylate (ACC1), indicating that HNRNPA2B1, as a carcinogenic factor, promotes the progression of ESCC by accelerating fatty acid synthesis, and may become a prognostic biomarker and therapeutic target of ESCC.

In addition, ALKBH5 and HNRNPA2B1 are effective indicators for predicting Overall Survival (OS) in patients with ESCC. High expression of HNRNPA2B1 and low expression of ALKBH5 are risk factors for ESCC survival. The combination of these two factors shows better predictive ability than using these two factors alone.

HNRNPC

Studies have shown that HNRNPC is overexpressed in ESCC tissues, and its expression is negatively correlated with the overall survival of patients with ESCC [34]. The double gene prognostic markers composed of ALKBH5 and HNRNPC have been proved to be a good predictor of survival outcome in ESCC.

m⁶A methylation as a therapeutic strategy for ESCC

More and more studies have found that microRNAs [35, 36] and circular RNAs [37] can be used as potential biomarkers for prognosis, diagnosis and treatment of EC. However, due to the high morbidity and mortality of EC, it is necessary to find new anticancer drugs, such as curcumin [38], which can be potentially used in chemotherapy and chemoprevention of EC by regulating miRNAs. Allicin [39] can achieve its anticancer effect by inhibiting cell growth and inducing apoptosis.

As described in Table 1, m⁶A plays different regulatory roles in ESCC through different biological functions. In addition, a study [40] constructed and verified prognostic markers of ESCC based on m⁶A RNA methylation regulators, which may be a promising tool for predicting patient survival and provide important information for ESCC to make diagnosis and treatment strategies.

In recent years, many studies have revealed that m⁶A plays an important role in the formation of many kinds of tumors, such as breast cancer [41, 42], ovarian cancer [43, 44], cervical cancer [45], acute myeloid leukemia [46‐48], glioblastomas [49‐51], non-small cell lung cancer [52‐55], hepatocellular cancer [56‐59], gastric cancer [60], colorectal cancer [61], pancreatic cancer [62], etc. Furthermore, it is found that m⁶A modification plays a key role in tumor radiotherapy, chemotherapy and drug therapy. Table 2 summarizes the mechanism and drug resistance of m⁶A regulatory factors in related tumors, which may provide clinical reference value and significance for the treatment of esophageal cancer in the future.

Table 2

Mechanism and drug resistance of m⁶A regulatory factor in related tumors

Related tumors	m⁶A regulator	Roles	Study model	Mechanism	Resistance	Ref.
Breast cancer	METTL3	Oncogene	In vitro: MCF-7	METTL3, hepatitis B virus X protein binding protein (HBXIP) and miRNA let-7 g form a positive feedback loop	Tamoxifen	[41]
Breast cancer	ALKBH5	Oncogene	In vivo: mice	Demethylation of NANOG and increase of mRNA level	Tamoxifen	[42]
Ovarian cancer	YTHDF1	Oncogene	In vitro: SKOV3, A2780	TRIM29 may be used as an oncogene	Cisplatin	[43]
Ovarian cancer	FTO/ALKBH5	Oncogene	In vitro: PEO1	Up-regulation of Wnt/ β-catenin pathway by stabilizing FZD1	Olaparib	[44]
Cervical cancer	FTO	Oncogene	In vitro: SiHa	Regulation of β-catenin/ERCC1 axis	–	[45]
Acute myeloid leukemia (AML)	METTL3	Oncogene	In vitro: MOLM13, THP-1, MV4-11, NOMO-1, HL-60, EOL-1, KG-1, RN2c, HEL, JURKA T, LOUCY, K562	Regulating the expression of c-Myc, Bcl-2 and PTEN	–	[46]
	METTL14	Oncogene	In vivo: human	Enhanced self-renewal of hematopoietic stem cells and inhibition of bone marrow cell differentiation through SPI1-METTL14-MYB/MYC axis	–	[47]
	WTAP	Oncogene	In vitro: K562,HL-60,OCI-AML3,Ba/F3	Regulating WT1 pathway to promote cell proliferation	–	[48]
Glioblastomas (GBMs)	METTL3	Oncogene	In vivo: human	Inhibition of tumorigenesis and self-renewal / proliferation of MSCs	Y- Irradiation	[49]
	METTL14	Suppressor	In vivo: human	It is possible to target ADAM19 to inhibit tumorigenesis and self-renewal / proliferation of glioma stem-like cells (GSCs)	–	[50]
	FTO	Oncogene	In vivo: human	The inhibitory effect of drugs on FTO can inhibit the formation of m⁶A demethylation gene in glioblastoma	–	[50]
	ALKBH5	Oncogene	In vivo: mice	Demethylated FOXM1 promotes tumorigenicity of GSC	–	[51]
Non-small cell lung cancer (NSCLC)	METTL3	Oncogene	In vitro: A549, H1299, Calu6,H520,95-D, PC9,HCC827	SUMO promotes tumor growth of lysine residues K177, K211, K212 and K215 in NSCLC	Cisplatin/ Gefitinib	[52, 53]
	WTAP	Oncogene	In vitro: H1299, A549, EBC-1, HCC827,CALU-3, H661,H596, H358, H460,H1650, H1975, H1395,H292	Down-regulation of c-MET expression	Crizotinib	[54]
	YTHDF1	Suppressor	In vitro: HEK-293T, H1975, A549, NCI-H838, H1299, NCI-H1650,GLC-82, SPC-A1	regulating the translational efficiency of CDK2, CDK4, and cyclin D1	Cisplatin	[55]
Hepatocellular cance	METTL3	Oncogene	In vitro: HepG2,Huh-7,MHCC97L, HepG-2,Hepa1-6, HEK-293T,WRL68, HUVEC,SMMC-7721, Bel7402,HepG-2, WRL68, HEK-293T	Reduce the stability of SOCS2 mRNA	Sorafenib	[56, 57]
	METTL14	Oncogene	In vivo: mice	Progress in regulating miR-126 through DGCR8	Sorafenib	[58]
	YTHDF2	Oncogene	In vitro: HepG2,293T	MiR-145 regulates m⁶A level by targeting YTHDF2 mRNA 3-UTR in hepatocellular carcinoma cells	–	[59]
Gastric cancer	METTL3	Suppressor	In vitro: AGS,HGC-27, MKN-45	mediated this process occurred on the A879 locus of pri-miR-17-92	Everolimus	[60]
Colorectal cancer	YTHDF1	Oncogene	In vitro: SW480,CaCO2, HT29, RKO,DLD-1, KM12SM, HCT-116,LoVo	C-Myc promotes the expression of YTHDF1 and affects the proliferation and chemosensitivity of colorectal cancer	Oxaliplatin/ 5-Fu	[61]
Pancreatic cancer	METTL3	Oncogene	In vitro: MIA PaCa-2	METTL3 is associated with mitogen-activated protein kinase cascades, ubiquitin-dependent process and RNA splicing and regulation of cellular process	Cisplatin/ Fu / Y-Irradiation	[62]

Although many scholars have reported the study of m⁶A modification in tumor therapy, because the mechanism of tumor formation is very complex, accurate m⁶A targeting therapy needs to be explored. By changing the m⁶A level of some specific genes corresponding to mRNA in cells, it affects the expression of a series of downstream oncogenes or transcription factors. It is possible that regulating the level of m⁶A in tumor cells will become the entry point of tumor radiotherapy, chemotherapy and drug therapy [63, 64]. There is still a long way to go in the treatment of tumor in the future.

Conclusion

In summary, with the development of biological techniques such as high-throughput sequencing, the role of m⁶A methylation in ESCC has been gradually revealed, at present, it has been found that there are abnormal expressions of METTL3, ALKBH5, FTO, YTHDC2, HNRNPA2B1 and HNRNPC in ESCC, mainly by affecting the stability of mRNA, regulating cancer cell proliferation and affecting tumor cell metastasis and invasion.

The discovery of m⁶A opens a new way for the study of epigenetics and tumor-related diseases, but the study of m⁶A modification is still in its infancy and there are still many challenges. the aim is to further study the role of epigenetic network in the occurrence and development of ESCC and to strengthen the evaluation of the safety and effectiveness of m⁶A-related regulatory factors and pathways as new targets for tumor therapy. To further explore the correlation between m⁶A and drug sensitivity and long-term prognosis of patients with ESCC, and to realize the application of m⁶A from basic research to clinical drug development as soon as possible.

Acknowledgements

None.

Declarations

Not applicable.

All authors have reviewed the manuscript and agree to publish it in its current form.

Competing interests

The authors declare no conflict of interest.

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Abnet CC, et al. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018;154:360–73.PubMedCrossRef

Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2015;65(1):5–29.PubMedCrossRef

Cheung WY, et al. Genetic variations in esophageal cancer risk and prognosis. Gastroenterol Clin North Am. 2009;38:75–91.PubMedCrossRef

Hassanabad AF, Chehade R, Breadner D, Raphael J. Esophageal carcinoma: towards targeted therapies. Cell Oncol. 2020;43(2):195–209.CrossRef

van Rossum PSN, Mohammad NH, Vleggaar FP, van Hillegersberg R. Treatment for unresectable or metastatic oesophageal cancer: current evidence and trends. Nat Rev Gastroenterol Hepatol. 2018;15:235–49.PubMedCrossRef

Abbas G, Krasna M. Overview of esophageal cancer. Ann Car-diothorac Surg. 2017;6(2):131.CrossRef

Zhao Y, Shi Y, Shen H, Xie W. m6A-binding proteins: the emerging crucial performers in epigenetics. Hematol Oncol. 2020;13:35.CrossRef

Kane SE, Beemon K. Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: Implications for RNA processing. Mol Cell Biol. 1985;5(9):2298–306.PubMedPubMedCentral

Zhang C, Fu J, Zhou Y. A review in research progress concerning m6A methylation and immunoregulation. Front Immunol. 2019;10:922.PubMedPubMedCentralCrossRef

10.

Bokar JA, et al. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997;3(11):1233–47.PubMedPubMedCentral

11.

Zhang S. Mechanism of N(6)-methyladenosine modification and its emerging role in cancer. Pharmacol Ther. 2018;189:173–83.PubMedCrossRef

12.

Liu N, Dai Q, Zheng G, et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518:560–4.PubMedPubMedCentralCrossRef

13.

Meyer KD, Jaffrey SR. Rethinking m(6)A readers, writers, and erasers. Annu Rev Cell Dev Biol. 2017;33:319–42.PubMedPubMedCentralCrossRef

14.

Chen XY, Zhang J, Zhu JS. The role of m(6)A RNA methylation in human cancer. Mol Cancer. 2019;18(1):103.PubMedPubMedCentralCrossRef

15.

Wang X, Lu Z, Gomez A, et al. N-6-methyladenosine -dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117–20.PubMedCrossRef

16.

Parashar NC, Parashar G, Nayyar H, et al. N6-adenine DNA methylation demystified in eukaryotic genome: From biology to pathology. Biochimie. 2018;144:56–62.PubMedCrossRef

17.

Edupuganti RR, Geiger S, Lindeboom RGH, et al. N- 6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat Struct Mol Biol. 2017;24(10):870.PubMedPubMedCentralCrossRef

18.

Wang Y, Li Y, Toth JI, et al. N6- methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol. 2014;16(2):191–8.PubMedPubMedCentralCrossRef

19.

Roundtree IA, Evans ME, Pan T, et al. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169(7):1187–200.PubMedPubMedCentralCrossRef

20.

Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18–29.PubMedCrossRef

21.

Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity- associated FTO. Nat Chem Biol. 2011;7(12):885–7.PubMedPubMedCentralCrossRef

22.

Gerken T, Girard CA, Tung YC, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318(5855):1469–72.PubMedPubMedCentralCrossRef

23.

Cardelli M, Marchegiani F, Cavallone L, et al. A polymorphism of the YTHDF2 gene (1p35) located in an Alu-rich genomic domain is associated with human longevity. J Gerontol A Biol Sci Med Sci. 2006;61(6):547–56.PubMedCrossRef

24.

Huang H, Weng H, Sun W, et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20(3):285–95.PubMedPubMedCentralCrossRef

25.

Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 2017;27:315–28.PubMedPubMedCentralCrossRef

26.

Xiao Y, Xue J, Zhang L, et al. Misalignment fault diagnosis for wind turbines based on information fusion. Entropy (Basel). 2021;23(2):243.CrossRef

27.

Nagaki Y, Motoyama S, Yamaguchi T, et al. m(6)A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis. Genes Cells. 2020;25(8):547–61.PubMedCrossRef

28.

Xue J, Xiao P, Yu X, Zhang X. A positive feedback loop between AlkB homolog 5 and miR-193a-3p promotes growth and metastasis in esophageal squamous cell carcinoma. Hum Cell. 2021;34(2):502–14.PubMedCrossRef

29.

Yang N, Ying P, Tian J, et al. Genetic variants in m6A modification genes are associated with esophageal squamous-cell carcinoma in the Chinese population. Carcinogenesis. 2020;41(6):761–8.PubMedCrossRef

30.

Xia TL, Li X, Wang X, et al. Upregulation of METTL3 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Manag Res. 2020;12:5729–37.PubMedPubMedCentralCrossRef

31.

Hu W, Liu W, Liang H, et al. Silencing of methyltransferase-like 3 inhibits oesophageal squamous cell carcinoma. Exp Ther Med. 2020;20(6):138.PubMedPubMedCentralCrossRef

32.

Liu S, Huang M, Chen Z, et al. FTO promotes cell proliferation and migration in esophageal squamous cell carcinoma through up-regulation of MMP13. Exp Cell Res. 2020;389(1):111894.PubMedCrossRef

33.

Guo H, Wang B, Xu K, et al. m6A reader HNRNPA2B1 promotes esophageal cancer progression via up-regulation of ACLY and ACC1. Front Oncol. 2020;10:553045.PubMedPubMedCentralCrossRef

34.

Xu LC, Pan JX, Pan HD. Construction and validation of an m6A RNA methylation regulators-based prognostic signature for esophageal cancer. Cancer Manag Res. 2020;12:5385–94.PubMedPubMedCentralCrossRef

35.

Pourhanifeh MH, Vosough M, Mahjoubin-Tehran M, et al. Autophagy-related microRNAs: possible regulatory roles and therapeutic potential in and gastrointestinal cancers. Pharmacol Res. 2020;161:105133.PubMedCrossRef

36.

Jamali L, Tofigh R, Tutunchi S, et al. Circulating microRNAs as diagnostic and therapeutic biomarkers in gastric and esophageal cancers. J Cell Physiol. 2018;233(11):8538–50.PubMedCrossRef

37.

Naeli P, Pourhanifeh MH, Karimzadeh MR, et al. Circular RNAs and gastrointestinal cancers: epigenetic regulators with a prognostic and therapeutic role. Crit Rev Oncol Hematol. 2020;145:102854.PubMedCrossRef

38.

Hesari A, Azizian M, Sheikhi A, et al. Chemopreventive and therapeutic potential of curcumin in esophageal cancer: current and future status. Int J Cancer. 2019;144(6):1215–26.PubMedCrossRef

39.

Sarvizadeh M, Hasanpour O, Naderi Ghale-Noie Z, et al. Allicin and digestive system cancers: from chemical structure to its therapeutic opportunities. Front Oncol. 2021;11:650256.PubMedPubMedCentralCrossRef

40.

Xu LC, Pan JX, Pan HD. Construction and validation of an m6A RNA methylation regulators-based prognostic signature for esophageal cancer. Cancer Manag Res. 2020;6(12):5385–94.CrossRef

41.

Liu X, Gonzalez G, Dai X, et al. Adenylate kinase 4 modulates the resistance of breast cancer cells to tamoxifen through an m6A-based epitranscriptomic mechanism. Mol Ther. 2020;28(12):2593–604.PubMedCrossRefPubMedCentral

42.

Zhang CZ, Samanta D, Lu HQ, et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. PNAS. 2016;113(14):E2047–56.PubMedPubMedCentralCrossRef

43.

Hao L, Wang JM, Liu BQ, et al. m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells. Biochim Biophys Acta Mol Cell Res. 2021;1868:118878.PubMedCrossRef

44.

Fukumoto T, Zhu H, Nacarelli T, et al. N(6)-methylation of adenosine of FZD10 mRNA contributes to PARP inhibitor resistance. Cancer Res. 2019;79:2812–20.PubMedPubMedCentralCrossRef

45.

Wang XL, Li ZH, Kong BH, et al. Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer. Oncotarget. 2017;8(58):98918–30.PubMedPubMedCentralCrossRef

46.

Barbieri I, Tzelepis K, Pandolfini L, et al. Promoter- bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 2017;552(7683):126–31.PubMedPubMedCentralCrossRef

47.

Vu LP, Pickering BF, Cheng YM, et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23(11):1369–76.PubMedPubMedCentralCrossRef

48.

Bansal H, Yihua Q, Iyer SP, et al. WTAP is a novel oncogenic protein in acute myeloid leukemia. Leukemia. 2014;28(5):1171–4.PubMedPubMedCentralCrossRef

49.

Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, et al. Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018;37:522–33.PubMedCrossRef

50.

Cui Q, Shi HL, Ye P, et al. m6A RNA methylation regulates the Self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017;18(11):2622–34.PubMedPubMedCentralCrossRef

51.

Zhang SC, Zhao BS, Zhou AD, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591-606.e6.PubMedPubMedCentralCrossRef

52.

Jin D, Guo J, Wu Y, et al. m(6)A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. Hematol Oncol. 2019;12:135.CrossRef

53.

Liu S, Li Q, Li G, et al. The mechanism of m(6)A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by beta-elemene. Cell Death Dis. 2020;11:969.PubMedPubMedCentralCrossRef

54.

Ding N, You A, Tian W, et al. Chidamide increases the sensitivity of Non-small Cell Lung Cancer to Crizotinib by decreasing c-MET mRNA methylation. Int J Biol Sci. 2020;16:2595–611.PubMedPubMedCentralCrossRef

55.

Shi Y, Fan S, Wu M, et al. YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun. 2019;10:4892.PubMedPubMedCentralCrossRef

56.

Chen MN, Wei L, Law CT, et al. RNA N6-methyladenosine methyl-transferase- like 3 promotes liver cancer progression through YTH-DF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2018;67(6):2254–70.PubMedCrossRef

57.

Lin Z, Niu Y, Wan A, Chen D, Liang H, Chen X, et al. RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J. 2020;39:e103181.PubMedPubMedCentralCrossRef

58.

Ma JZ, Yang F, Zhou CC, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methylade-nosine-dependent primary Micro RNA processing. Hepatology. 2017;65(2):529–43.PubMedCrossRef

59.

Yang Z, Li J, Feng GX, et al. MicroRNA-145 modulates N6-methy-ladenosine levels by targeting the 3’- untranslated mRNA region of the N6-methyladenosine binding YTH domain family 2 protein. J Biol Chem. 2017;292(9):3614–23.PubMedPubMedCentralCrossRef

60.

Sun Y, Li S, Yu W, et al. N(6)-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer. Cell Death Dis. 2020;11:836.PubMedPubMedCentralCrossRef

61.

Nishizawa Y, Konno M, Asai A, et al. Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer. Oncotarget. 2018;9(7):7476–86.PubMedCrossRef

62.

Taketo K, Konno M, Asai A, et al. The epitranscriptome m6A writer METTL3 promotes chemo and radioresistance in pancreatic cancer cells. Int J Oncol. 2018;52:621–9.PubMed

63.

Wang S, Sun C, Li J, et al. Roles of RNA methylation by means of N6-methyladenosine (m6A) in human cancers. Cancer Lett. 2017;408:112–20.PubMedCrossRef

64.

Schwartz S, Mumbach MR, Jovanovic M, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Rep. 2014;8:284–96.PubMedPubMedCentralCrossRef

Titel: Recent advances of m6A methylation modification in esophageal squamous cell carcinoma
verfasst von: Xiaoqing Zhang
Ning Lu
Li Wang
Yixuan Wang
Minna Li
Ying Zhou
Manli Cui
Mingxin Zhang
Lingmin Zhang
Publikationsdatum: 01.12.2021
Verlag: BioMed Central
Erschienen in: Cancer Cell International / Ausgabe 1/2021
Elektronische ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-021-02132-2

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Recent advances of m⁶A methylation modification in esophageal squamous cell carcinoma

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