YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma.
YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma.
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YTHDF2通过识别METTL3介导的m(6)A修饰促进UBXN1 mRNA降解，从而激活NE-kappa B并促进胶质瘤的恶性进展
DOI：
10.1186/s13045-021-01124-z
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发表时间：
2021-07-10
影响因子：
28.5
通讯作者：
Wang YZ
中科院分区：
文献类型：
--
作者：
Chai RC;Chang YZ;Chang X;Pang B;An SY;Zhang KN;Chang YH;Jiang T;Wang YZ
弥漫性胶质瘤的预后非常差，其恶性进展的机制仍不清楚。本文旨在阐明RNA N6，2′-O-二甲基腺苷（m6 A）阅读器YTH N6-甲基腺苷RNA结合蛋白2（YTHDF 2）在调节胶质瘤恶性进展中的作用和机制。 使用几个独立的数据集评估YTHDF 2 mRNA水平和功能。采用Western blotting、定量聚合酶链反应和免疫组织化学方法检测YTHDF 2和其他分子在人和小鼠肿瘤组织和细胞中的表达水平。在细胞和原位异种移植物模型中，使用敲低和过表达来评估YTHDF 2、甲基转移酶样3（methyltransferase-like 3，瘤L3）和UBX结构域蛋白1（UBXN 1）对胶质瘤恶性度的影响。进行RNA免疫沉淀（RIP）、甲基化RIP和RNA稳定性实验以研究YTHDF 2的致癌作用的潜在机制。YTHDF 2表达与胶质瘤恶性程度、分子亚型及预后有关。在体外和体内模型中，YTHDF 2促进了胶质瘤的恶性进展。YTHDF 2通过胃L3介导的m6 A促进UBXN 1 mRNA降解，进而促进NF-κB活化。我们进一步发现UBXN 1过表达减弱了YTHDF 2过表达的致癌作用，并与YTHDF 2表达升高的患者的生存率更高相关。我们的研究结果证实YTHDF 2促进胶质瘤的恶性进展，并揭示了重要的洞察NF-κB激活通过UBXN 1的上游调控机制，主要集中在m6 A修饰。在线版本包含补充材料，可通过10.1186/s13045-021-01124-z获得。
The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2′-O-dimethyladenosine (m6A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas. YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2. YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m6A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression. Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m6A modification. The online version contains supplementary material available at 10.1186/s13045-021-01124-z.
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