The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells
The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells
复制标题
m(6)A 甲基化调节的 AFF4 促进膀胱癌干细胞的自我更新。
DOI：
10.1155/2020/8849218
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发表时间：
2020-07-02
影响因子：
4.3
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Gao, Qian;Zheng, Jin;Li, Yang
N-6-甲基腺苷(m(6)A)对mRNA的动态修饰在调节基因表达和决定细胞命运方面起着重要作用。然而，m(6)AmRNA修饰在膀胱癌干细胞(BCSCs)中的作用尚未被描述。在这里，我们发现在膀胱癌(BCA)细胞中，整体RNA m(6)A丰度和m(6)A形成酶METTL3的表达高于非膀胱癌细胞。METTL3的缺失抑制了BCSCs的自我更新，表现为ALDH活性和球体形成能力的降低。在机制上，METTL3调节m(6)A修饰，从而调节AF4/FMR2家族成员4(AFF4)的表达，而AFF4的敲除现象复制了METTL3的去除，降低了BCSC在体内的致瘤能力。AFF4结合于启动子区并支持SOX2和MYC的转录，而SOX2和MYC在BCSCs中具有重要的生物学功能。总而言之，我们的结果证明了m(6)A修饰通过一个新的信号轴METTL3-AFF4-SOX2/MYC在BCSCs自我更新和致瘤性中的关键作用。
The dynamic N-6-methyladenosine (m(6)A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m(6)A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m(6)A abundance and the expression of m(6)A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m(6)A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCsin vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m(6)A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC.