RNA m<sup>6</sup>A甲基化修饰调控异常在乳腺癌转移中作用的研究新进展

doi:10.3877/cma.j.issn.2095-1221.2023.01.006

乳腺癌转移是导致患者生存预后差的重要原因，目前对其分子机制的认识仍有限。RNA N⁶-甲基腺苷（m⁶A）甲基化修饰是近十余年颇受关注的基因转录后水平表观调控新机制，它在乳腺癌转移等恶性生物学中的重要作用也日益凸显。特定RNA的m⁶A甲基化修饰主要受甲基转移酶复合体（MTC）和RNA去甲基酶影响，如肥胖相关蛋白（FTO）等动态调控；而m⁶A甲基化修饰后的RNA还需要"解读"蛋白对其的解析才能进一步发挥特定的生物学功能。本综述总结了介导RNA m⁶A甲基化修饰的"写入蛋白"、"擦除蛋白"和"解读蛋白"等各组分调控异常在乳腺癌转移中的作用及其相关分子机制方面的研究新进展，并就未来乳腺癌转移的RNA m⁶A甲基化修饰失调控的精准检测和基于新分子机制的靶向治疗新策略开发作一展望。

关键词: N⁶-甲基腺苷（m⁶A）, RNA m⁶A修饰, 乳腺癌, 肿瘤转移, 表观转录组

Metastasis is an important cause of poor survival and prognosis of patients with breast cancer; however, our current knowledge of its underlying molecular mechanism is limited. RNA N⁶-methyladenosine (m⁶A) modification is a novel mechanism of epi-transcriptional regulation of gene expression at the posttranscriptional level that has attracted much attention in the past decade. Its important role in malignant biology such as breast cancer metastasis is emerging now. The m⁶A modification of specific RNA is dynamically regulated by the methyltransferase complex (MTC) and RNA demethylases such as fat mass and obesity-associated protein (FTO) . The biological function of RNA that has undergone the m⁶A modification depends on the interpretation of its ''reader'' protein. This review summarizes the latest research progress in the role of dysregulated various components of RNA m⁶A modification including m⁶A ''writers'', ''erasers'' and ''readers'' in breast cancer metastasis as well as their underlying molecular mechanisms. Meanwhile, the future directions of development of precise detection of dysregulated RNA m⁶A modification in breast cancer metastasis and new targeted therapy strategies based on novel molecular mechanisms are also prospected.

Key words: N⁶-methyladenosine (m⁶A), RNA m⁶A modification, Breast cancer, Tumor metastasis, Epitranscriptome

图1 RNA m⁶A甲基化动态修饰过程及其生物学功能解析模式^{[16,18,19,20]}注：RNA为核糖核酸；m⁶A为N⁶-甲基腺苷；METTL3为甲基转移酶样蛋白3；METTL14为甲基转移酶样蛋白14；WTAP为肾母细胞瘤1相关蛋白；ZC3H13为含CCCH锌指蛋白13；RBM15/RBM15B为RNA结合模体蛋白15/15B；FTO为肥胖相关蛋白；ALKBH5为AlkB同源蛋白5；YTHDC1/2和YTHDF1/2/3分别为YTH结构域家族成员C1/2和F1/2/3；IGF2BP1/2/3为胰岛素样生长因子2 mRNA结合蛋白家族成员1/2/3；hnRNPC、hnRNPG和hnRNPCA2B1分别为核不均一性核糖核蛋白家族成员C、G和A2B1

图2 RNA m⁶A甲基化修饰失调控在乳腺癌转移中的作用注：MALAT1为转移相关肺腺癌转录本-1；KRT7为角蛋白7；SOX2为SRY-盒2；COL3A1为III型胶原蛋白α1链；CXCR4为趋化因子受体4；SMC1A为染色体结构稳定蛋白1A；NANOG为NANOG同源框蛋白；BNIP3为Bcl-2/E1B-19kDa相互作用蛋白3；APC2为结肠腺瘤性息肉病基因2；AXIN1为轴蛋白1；SMAD3为SMAD家族成员3；FOXM1为叉头盒M1；PKM2为丙酮酸激酶M2；ST6GALNAC5为α2, 6-唾液酰转移酶；ZEB1为锌指E盒结合同源框1；HSPD1为热休克蛋白家族D成员1；RBM8A为RNA结合基元蛋白8A；G3BP1为GTP酶活化蛋白结合蛋白1；PR为孕激素受体；PFN2为肌动蛋白抑制蛋白2

表1 RNA m⁶A甲基化修饰各组分在乳腺癌转移中的作用及其调控靶基因概览

RNA m⁶A甲基化修饰组分	乳腺癌组织中表达水平	乳腺癌转移中的作用	调控的靶基因	参考文献
RNA m⁶A"写入蛋白"
METTL3	高	促进转移	MALAT1、KRT7、SOX2	[26，27，28，29，30]
	低	抑制转移	COL3A1	[33]
METTL14	低	抑制转移	未知	[36，37，38]
	高	促进转移	CXCR4	[39]
WTAP	高	抑制转移	未知	[40]
KIAA1429（VIRMA）	高	促进转移	SMC1A	[41，42]
RNA m⁶A"擦除蛋白"
FTO	高	促进转移	BNIP3、miR-181b-3p	[43，44]
	低	抑制转移	APC2、AXIN1	[45]
ALKBH5	高	促进转移	NANOG	[49，50，51]
RNA m⁶A"解读蛋白"
YTHDC1	高	促进转移	SMAD3	[59]
YTHDC2	未知	未知	未知	-
YTHDF1	高	促进转移	FOXM1、PKM2	[61，62]
YTHDF2	低	抑制转移	未知	[56]
YTHDF3	高	促进转移	ST6GALNAC5、ZEB1	[57，58]
IGF2BP1	高	促进转移	lncRNA MIR210HG	[65]
IGF2BP2	高	促进转移	HSPD1、RBM8A、G3BP1	[55]
IGF2BP3	高	促进转移	PR	[54]
hnRNPC	高	促进转移	未知	[70，71，72]
hnRNPA2B1	低	抑制转移	PFN2	[76]

表1 RNA m⁶A甲基化修饰各组分在乳腺癌转移中的作用及其调控靶基因概览

RNA m⁶A甲基化修饰组分	乳腺癌组织中表达水平	乳腺癌转移中的作用	调控的靶基因	参考文献
RNA m⁶A"写入蛋白"
METTL3	高	促进转移	MALAT1、KRT7、SOX2	[26，27，28，29，30]
	低	抑制转移	COL3A1	[33]
METTL14	低	抑制转移	未知	[36，37，38]
	高	促进转移	CXCR4	[39]
WTAP	高	抑制转移	未知	[40]
KIAA1429（VIRMA）	高	促进转移	SMC1A	[41，42]
RNA m⁶A"擦除蛋白"
FTO	高	促进转移	BNIP3、miR-181b-3p	[43，44]
	低	抑制转移	APC2、AXIN1	[45]
ALKBH5	高	促进转移	NANOG	[49，50，51]
RNA m⁶A"解读蛋白"
YTHDC1	高	促进转移	SMAD3	[59]
YTHDC2	未知	未知	未知	-
YTHDF1	高	促进转移	FOXM1、PKM2	[61，62]
YTHDF2	低	抑制转移	未知	[56]
YTHDF3	高	促进转移	ST6GALNAC5、ZEB1	[57，58]
IGF2BP1	高	促进转移	lncRNA MIR210HG	[65]
IGF2BP2	高	促进转移	HSPD1、RBM8A、G3BP1	[55]
IGF2BP3	高	促进转移	PR	[54]
hnRNPC	高	促进转移	未知	[70，71，72]
hnRNPA2B1	低	抑制转移	PFN2	[76]

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Research progress in the role of dysregulated RNA m⁶A modification in breast cancer metastasis

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Research progress in the role of dysregulated RNA m6A modification in breast cancer metastasis

Research progress in the role of dysregulated RNA m⁶A modification in breast cancer metastasis