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Recent Advances of M6a Methylation Modification in Esophageal Squamous Cell Carcinoma

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Recent Advances of M6a Methylation Modification in Esophageal Squamous Cell Carcinoma Zhang et al. Cancer Cell Int (2021) 21:421 https://doi.org/10.1186/s12935-021-02132-2 Cancer Cell International REVIEW Open Access Recent advances of m6A methylation modifcation in esophageal squamous cell carcinoma Xiaoqing Zhang1†, Ning Lu1†, Li Wang2†, Yixuan Wang1, Minna Li1, Ying Zhou3, Manli Cui1*, Mingxin Zhang1,3* and Lingmin Zhang4* Abstract In recent years, with the development of RNA sequencing technology and bioinformatics methods, the epigenetic modifcation of RNA based on N6-methyladenosine (m6A) has gradually become a research hotspot in the feld of bioscience. m6A is the most abundant internal modifcation in eukaryotic messenger RNAs (mRNAs). m6A methylation modifcation 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 modifcation level to afect 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. Keywords: N6-methyladenosine, Methylation, Esophageal squamous cell carcinoma Introduction surgical resection, combined radiotherapy and chemo- Esophageal cancer (EC) is one of the most invasive malig- therapy have improved the prognosis of patients with nant tumors of digestive tract in the world, and its mor- ESCC, the 5-year overall survival rate is still very low [5], bidity and mortality are still high in China [1]. 90% of the between 20 and 30% [6]. Terefore, there is an urgent histopathological types of esophageal cancer are esopha- need to fnd new diagnostic biomarkers and potential geal squamous cell carcinoma (ESCC) [2]. EC is caused therapeutic targets for ESCC patients. by a variety of causes, among which genetic and epige- In recent years, with the continuous development of netic modifcations play a key role in the occurrence and tumor epigenetics, N6-methyladenine (m6A) has not only development of ESCC [3, 4]. In recent years, although initiated a new era of post-transcriptional gene regula- tion in eukaryotes, but also rapidly become a research hotspot in the feld of RNA methylation modifcation. As *Correspondence: [email protected]; [email protected]; 6 [email protected] a reversible RNA methylation modifcation, m A meth- †Co-frst author: Xiaoqing Zhang, Ning Lu, and Li Wang contributed ylation is dynamically regulated by a variety of regulatory equally to this work 6 1 Department of Gastroenterology, The First Afliated Hospital of Xi’an factors [7]. Te imbalance of m A methylation regula- Medical University, No. 48 Feng Hao West Road, Xi’an 710077, Shaanxi, tors changes the biological functions of cell proliferation, China migration and invasion, and fnally leads to the occur- 4 Department of Anesthesiology, First Afliated Hospital, Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an 710061, China rence and development of tumor. Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Cancer Cell Int (2021) 21:421 Page 2 of 9 Tis article reviews the related concepts and biological m6A is involved in many cellular RNA processes, functions of m6A methylation and the research progress including transcription, splicing, nuclear transport, in ESCC. In addition, it also emphasizes the prospect translation and degradation [12, 15]. By afecting the sta- of m6A methylation as a new diagnostic biomarker and bility and half-life of mRNA, m6A regulates gene expres- potential therapeutic target for ESCC. sion and regulates important biological functions such as mammalian reproductive function, circadian rhythm, 6 Related concepts and biological functions of m A adipogenesis and human lifespan [16]. Its interference methylation may afect gene table regulation and cell biological func- m6A refers to the methylation at the N6 position of aden- tion [17], and indirectly afect the stability and half-life of osine, which is mainly concentrated in the 3’untranslated mRNA, leading to tumors and many diseases. Te basic region near the mRNA Terminator. m6A modifcation mechanism of m 6A methylation in RNA is shown in mainly occurs in the RRm6ACH sequence [8]. As one of Fig. 1. the most common and abundant internal modifcations 6 in mammals and eukaryotes [9], m6A RNA modifcation m A modifed writing gene (writers) involves almost all aspects of RNA metabolism [10]. Its Te written genes are various methyltransferases that regulation process is mainly dynamically and reversibly promote m6A RNA methylation modifcation. At pre- regulated by a variety of regulatory factors. Te methyl- sent, the components identifed by m6A methyltrans- ated proteins involved in m 6A methylation are mainly ferase include methyltransferase like 3 (METTL3), methyltransferases, demethylases and RNA binding pro- METTL14, Wilms’ tumor 1 associated protein (WTAP), teins [11–13]. Tey can add, remove or give priority to and Virilizer like m6A methyltransferase associated pro- recognize m6A sites, which play a key regulatory role tein (VIRMA/KIAA1429), RNA binding motif protein 15 in the expression of the whole genome and have a great (RBM15), zinc fnger CCCH domain-containing protein impact on normal physiological function or pathological 13 (ZC3H13), Casitas B-lineage lymphoma-transforming status [14]. sequence-like protein 1, CBLL1/HAKAI). Fig. 1 Basic mechanism of m6A methylation in RNA. Basic mechanism of m6A. The m6A methylation is catalyzed by the writer complex including METTL3, METTL14, WTAP, VIRMA, RBM15, ZC3H13 and CBLL1. The m6A modifcation is removed by demethylase FTO or ALKBH5. Reader proteins recognize m6A and determine target RNA nature Zhang et al. Cancer Cell Int (2021) 21:421 Page 3 of 9 Methyltransferase mainly forms stable complexes the translation of target mRNA. Among them, YTHDF3 through core proteins such as METTL3, METTL14 and can assist YTHDF1 to jointly promote the translation of W TA P. m 6A methylation occurs on the bases of mRNA related mRNA [25]. [18], in which METTL3 is a subunit with catalytic activ- 6 ity, METTL14 is responsible for recognizing the sub- The role and signifcance of m A methylation strate, WATP is mainly responsible for assisting METTL3 in ESCC and METTL14 to target to nuclear spots, and WTAP has Studies have shown that m 6A modifed mRNA is mal- independent methylation sites, which can make some adjusted in many cancers, and its role in cancer has 6 m A sites specifc methylation. VIRMA/KIAA1429, been gradually confrmed in vivo and in vitro, not only another component of methyltransferase complex, is a non-coding "writing genes", "erasing genes" and "read- protein involved in alternative splicing and interacts with ing genes", but also other protein factors, including W TA P. oncogenes, transcription factors and signal transduc- tion factors. the overexpression or consumption of these 6 m A modifed eraser gene (erasers) m6A-related factors may change the m6A modifcation in Te erase gene can remove the m 6A modifcation in the the tumor and interfere with the progression of cancer. RNA molecule by encoding m6A demethylase, which Te role of m6A regulatory factor in ESCC is shown in is the key to the reversible process of m 6A modifca- Table 1. Terefore, to clarify the molecular mechanism of tion [19]. m6A demethylase has been identifed as AlkB these changes of m6A modifed RNA and identifying the homolog 5 (ALKBH5) [20] and fat mass and obesity asso- abnormal expression of m6A regulatory factors in clini- ciated (FTO) [21]. Although they have similar functions, cal biopsy specimens. It is of great signifcance for early but the action process is diferent. diagnosis of tumors, prediction of tumor prognosis and ALKBH5 can catalyze the m6A modifcation demeth- provision of new approaches of tumor treatment. ylation of RNA in vitro [20], which can signifcantly afect the output of mRNA and RNA metabolism as well as the 6 assembly of mRNA processing factors in nuclear spots. m A modifcation related protein was downregulated FTO has the function of demethylation of m6A on single- in ESCC. stranded DNA and RNA, and they are highly expressed ALKBH5 in fat, brain and hypothalamus [22], which is vital to Previous studies [26] have found that, the expression metabolism. of ALKBH5 in EC tissue decreased. Functional analysis showed that ALKBH5 could inhibit the proliferation, m6A modifed reading protein (readers) migration and invasion of EC cells. However, a recent Te protein that selectively binds to the post-transcrip- study found that ALKBH5 promotes the proliferation tional product of m 6A is called m 6A reading protein. At and migration of ESCC [27].
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