O-GlcNAcylation of YTHDF2 antagonizes ERK-dependent phosphorylation and inhibits lung carcinoma

IF 6.3 3区综合性期刊 Q1 Multidisciplinary

Fundamental Research Pub Date : 2025-09-01 DOI:10.1016/j.fmre.2024.07.003

Jie Li , Wen Zhou , Jianzhi Zhang , Li Ma , Zhuan Lv , Yiqun Geng , Xing Chen , Jing Li

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Abstract

The intracellular O-linked N-acetylglucosamine (O-GlcNAc) glycosylation mediates many signal transduction events and regulates tumorigenesis. Previously the RNA N6-methyladenosine (m⁶A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), has been shown to be O-GlcNAcylated on Ser-263 during Hepatitis B virus (HBV) infection and promote HBV-related hepatocellular carcinoma. Herein we mapped YTHDF2 O-GlcNAcylation at Thr-49 via electron-transfer dissociation mass spectrometry under unperturbed conditions. We show that YTHDF2 Thr-49 O-GlcNAcylation antagonizes Extracellular-signal regulated kinase (ERK)-dependent phosphorylation at Ser-39 and promotes YTHDF2 degradation. The downstream signaling pathway of YTHDF2 in lung carcinoma is thus upregulated, which leads to the downregulation of c-Myc. We further used mouse xenograft models to show that YTHDF2-T49A mutants increased lung cancer mass and size. Our work reveals a key role of YTHDF2 O-GlcNAcylation in tumorigenesis and suggests that O-GlcNAcylation exerts distinct functions under different biological stress.

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YTHDF2的o - glcn酰化可拮抗erk依赖性磷酸化并抑制肺癌

细胞内o -连接n -乙酰氨基葡萄糖（O-GlcNAc）糖基化介导许多信号转导事件并调节肿瘤发生。先前，RNA n6 -甲基腺苷（m6A）阅读器YTH （YT521-B同源）结构域2 （YTHDF2）已被证明在乙型肝炎病毒（HBV）感染期间Ser-263上发生o - glcn酰化，并促进HBV相关的肝细胞癌。在此，我们通过电子转移解离质谱在无扰动条件下绘制了YTHDF2在Thr-49上的o - glcn酰化。研究表明，YTHDF2 Thr-49 o - glcn酰化可拮抗细胞外信号调节激酶（ERK）依赖性Ser-39位点的磷酸化，并促进YTHDF2降解。因此，肺癌中YTHDF2下游信号通路上调，导致c-Myc下调。我们进一步使用小鼠异种移植模型表明，YTHDF2-T49A突变体增加了肺癌的质量和大小。我们的工作揭示了YTHDF2 o - glcn酰化在肿瘤发生中的关键作用，并表明o - glcn酰化在不同的生物胁迫下发挥不同的功能。

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