RNA m6A甲基化修饰酶调控肿瘤的功能及其抑制剂的研究进展

doi:10.3969/j.issn.1674-8115.2021.06.018

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (6): 809-814.doi: 10.3969/j.issn.1674-8115.2021.06.018

RNA m⁶A甲基化修饰酶调控肿瘤的功能及其抑制剂的研究进展

郝亚娟¹^,²(), 刘颖斌²^,³()

^1.上海交通大学医学院附属新华医院普外科，上海市胆道疾病研究中心，上海 200092
^2.上海市胆道疾病研究重点实验室，上海 200092
^3.上海交通大学医学院附属仁济医院胆胰外科，癌基因与相关基因国家重点实验室，上海市肿瘤研究所，上海 200120

出版日期:2021-06-28 发布日期:2021-06-29
通讯作者: 刘颖斌 E-mail:haoyajuan1989@126.com;laoniulyb@shsmu.edu.cn
作者简介:郝亚娟(1989—)，女，博士后，博士；电子信箱：haoyajuan1989@126.com。
基金资助:
上海市科学技术委员会启明星计划(19QA1405900);国家自然科学基金(31701124);上海市科学技术委员会重点实验室项目(17DZ2260200)

Research progress of RNA m⁶A methylation modification in regulating tumor function and its inhibitors

Ya-juan HAO¹^,²(), Ying-bin LIU²^,³()

^1.Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Research Center of Biliary Tract Disease, Shanghai 200092, China
^2.Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
^3.Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Oncogenes and Related Genes; Shanghai Cancer Institute, Shanghai 200120, China

Online:2021-06-28 Published:2021-06-29
Contact: Ying-bin LIU E-mail:haoyajuan1989@126.com;laoniulyb@shsmu.edu.cn
Supported by:
Rising-Star Program of Science and Technology Committee of Shanghai Municipality(19QA1405900);National Natural Science Foundation of China(31701124);Shanghai Key Laboratory Project of Science and Technology Committee of Shanghai Municipality(17DZ2260200)

摘要/Abstract

摘要：

RNA修饰在生命活动和疾病的发生和发展中发挥着重要的作用。氮6-甲基腺嘌呤（N⁶-methyladenine， m⁶A）修饰是信使RNA中广泛存在的甲基化修饰，是动态变化的。近年来在肿瘤中发现m⁶A修饰酶和结合蛋白表达异常，可通过改变靶基因的RNA m⁶A修饰水平来调控肿瘤的进展。该文综述了m⁶A的去甲基化酶和甲基转移酶，包括α-酮戊二酸依赖的加双氧酶FTO（FTO α-ketoglutarate dependent dioxygenase）、AlkB同源蛋白5（AlkB homolog 5，ALKBH5），甲基转移酶样3（methyltransferase like 3，METTL3）在多种肿瘤中发挥的重要功能，以及m⁶A修饰酶的小分子抑制剂的研究进展。

关键词: 氮6-甲基腺嘌呤（m⁶A）, 肿瘤, 抑制剂, α-酮戊二酸依赖的加双氧酶FTO

Abstract:

RNA modifications play an important role in physiology and pathology. N⁶-methyladenine (m⁶A) has been identified as a prevalent methylation modification on eukaryotic RNAs. RNA m⁶A can be reversible. In recent years, abnormal expression of the RNA m⁶A modification enzymes and binding proteins have been found in tumors, and they promote or inhibit the tumor progression by altering the mRNA m⁶A modification levels of the target genes. This paper reviews the important functions of FTO α-ketoglutarate dependent dioxygenase, AlkB homolog 5 (ALKBH5) and methyltransferase like 3 (METTL3) in a variety of tumors, and also reports their small molecule inhibitors.

Key words: RNA N⁶-methyladenine (m⁶A), tumor, inhibitor, FTO α-ketoglutarate dependent dioxygenase

中图分类号:

Q522

郝亚娟, 刘颖斌. RNA m⁶A甲基化修饰酶调控肿瘤的功能及其抑制剂的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(6): 809-814.

Ya-juan HAO, Ying-bin LIU. Research progress of RNA m⁶A methylation modification in regulating tumor function and its inhibitors[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(6): 809-814.

图/表 1

参考文献 40

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Inhibitor	Mode of action	Reference
MA	MA selectively inhibits FTO demethylation of m⁶A over ALKBH5. MA is a non-steroidal anti-inflammatory drug and mechanistic studies indicate it competes with FTO binding to the m⁶A-containing nucleic acid	[20]
Entacapone	Entacapone directly binds to FTO and inhibites FTO activity in vitro. Entacapone administration reduces body weight and lowers fasting blood glucose concentrations in diet-induced obese mice. FOXO1 mRNA acts as a direct substrate of FTO, and entacapone elicits its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis	[21]
FB23 and FB23-2	FB23 and FB23-2 directly bind to FTO and selectively inhibit FTO's m⁶A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human AML cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice	[22]
Rhein	Rhein is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binding to the FTO-active site in vitro. Rhein also exhibits good inhibitory activity on m⁶A demethylation inside cells	[23-24]
4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol（CHTB）	CHTB is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner	[25]
N-phenyl-1H-indol-2-amine derivatives	N-phenyl-1H-indol-2-amine derivative MU06 shows stable interaction with Arg96 and His231 residue of FTO protein throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) are found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking	[26]
Radicicol	Radicicol is a potent FTO inhibitor, and exhibits a dose-dependent inhibition of FTO demethylation activity with an IC₅₀ value of 16.04 μmol/L. Further ITC experiments show that the binding between radicicol and FTO is mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site	[27]
Nafamostat mesilate	Nafamostat mesilate is a serine protease inhibitor and used for the treatment of pancreatitis and cancers. The binding of nafamostat mesilate to FTO is driven by higher positive entropy changes and smaller negative enthalpy changes	[28]
Clausine E	The binding of Clausine E to FTO is driven by positive entropy and negative enthalpy changes. Results also indicate that the hydroxyl group is crucial for the binding of small molecules with FTO	[29]
2‐phenyl‐1H‐benzimidazole analogues	The binding between 2-phenyl-1H-benzimidazole structural analogue 6-chloro-2-phenyl-1H-benzimidazole (1 d) and FTO is dominated by entropy. Results of enzymatic activity assays provide an IC₅₀ value of 24.65 μmol/L for 1 d. The chlorine atom is crucial for the binding of small molecules with FTO	[30]

Inhibitor	Mode of action	Reference
MA	MA selectively inhibits FTO demethylation of m⁶A over ALKBH5. MA is a non-steroidal anti-inflammatory drug and mechanistic studies indicate it competes with FTO binding to the m⁶A-containing nucleic acid	[20]
Entacapone	Entacapone directly binds to FTO and inhibites FTO activity in vitro. Entacapone administration reduces body weight and lowers fasting blood glucose concentrations in diet-induced obese mice. FOXO1 mRNA acts as a direct substrate of FTO, and entacapone elicits its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis	[21]
FB23 and FB23-2	FB23 and FB23-2 directly bind to FTO and selectively inhibit FTO's m⁶A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human AML cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice	[22]
Rhein	Rhein is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binding to the FTO-active site in vitro. Rhein also exhibits good inhibitory activity on m⁶A demethylation inside cells	[23-24]
4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol（CHTB）	CHTB is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner	[25]
N-phenyl-1H-indol-2-amine derivatives	N-phenyl-1H-indol-2-amine derivative MU06 shows stable interaction with Arg96 and His231 residue of FTO protein throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) are found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking	[26]
Radicicol	Radicicol is a potent FTO inhibitor, and exhibits a dose-dependent inhibition of FTO demethylation activity with an IC₅₀ value of 16.04 μmol/L. Further ITC experiments show that the binding between radicicol and FTO is mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site	[27]
Nafamostat mesilate	Nafamostat mesilate is a serine protease inhibitor and used for the treatment of pancreatitis and cancers. The binding of nafamostat mesilate to FTO is driven by higher positive entropy changes and smaller negative enthalpy changes	[28]
Clausine E	The binding of Clausine E to FTO is driven by positive entropy and negative enthalpy changes. Results also indicate that the hydroxyl group is crucial for the binding of small molecules with FTO	[29]
2‐phenyl‐1H‐benzimidazole analogues	The binding between 2-phenyl-1H-benzimidazole structural analogue 6-chloro-2-phenyl-1H-benzimidazole (1 d) and FTO is dominated by entropy. Results of enzymatic activity assays provide an IC₅₀ value of 24.65 μmol/L for 1 d. The chlorine atom is crucial for the binding of small molecules with FTO	[30]

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RNA m⁶A甲基化修饰酶调控肿瘤的功能及其抑制剂的研究进展

Research progress of RNA m⁶A methylation modification in regulating tumor function and its inhibitors

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