METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma
METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma
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METTL3通过m6A修饰在HuR的协助下增强MALAT1的稳定性并激活NF-kappa B促进IDH野生型胶质瘤的恶性进展
DOI：
10.1016/j.canlet.2021.04.020
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发表时间：
2021-05-04
期刊：
影响因子：
9.7
通讯作者：
Wang, Yong-Zhi
中科院分区：
文献类型：
--
作者：
Chang, Yu-Zhou;Chai, Rui-Chao;Wang, Yong-Zhi
了解N6-甲基腺苷（m6 A）在肿瘤发生和干细胞维持中的作用是胶质瘤研究中的一个新兴领域。然而，有必要分别研究m6 A在IDH突变和IDH野生型胶质瘤中的功能。在此，我们的目的是阐明m6 A写入器L3在调节IDH野生型胶质瘤恶性进展中的作用和机制。我们证明了IDH野生型胶质瘤中，胃L3表达与较高的恶性度和较差的预后呈正相关，而IDH突变型胶质瘤则无此相关性。在体外和体内模型中，胃L3也可以促进胶质瘤的恶性进展。从机制上讲，MAL 3通过m6 A修饰增强其稳定性来上调MALAT 1表达。我们进一步揭示了HuR对于胃L3介导的MALAT 1稳定是必需的，并且上调的MALAT 1随后激活NF-κ B B。综上所述，我们的研究结果证实了胃L3促进了IDH-野生型胶质瘤的恶性进展，并揭示了对MALAT 1和NF-κ B上游调控机制的重要见解，主要集中在m6 A修饰上。
Understanding the role of N6-methyladenosine (m6A) in tumorigenesis and stem cell maintenance is an emerging field in glioma research. However, it is necessary to study the function of m6A in IDH-mutation and IDH-wildtype gliomas separately. Here, we aimed to elucidate the role and mechanism of the m6A writer METTL3 in regulating the malignant progression of IDH-wildtype gliomas. We demonstrated that METTL3 expression is positively associated with a higher malignant grade and poorer prognosis of IDH-wildtype gliomas but not IDH-mutant gliomas. METTL3 could also promote the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, METTL3 upregulated MALAT1 expression by enhancing its stability via m6A modification. We further revealed that HuR was essential for METTL3-mediated MALAT1 stabilization, and upregulated MALAT1 subsequently activated NF-kappa B. Taken together, our findings confirmed that METTL3 promoted the malignant progression of IDH-wildtype gliomas and revealed important insight into the upstream regulatory mechanism of MALAT1 and NF-kappa B with a primary focus on m6A modification.