O-GlcNAcylation of YTHDF2 antagonizes ERK-dependent phosphorylation and inhibits lung carcinoma
Year: 2024
Type: article
Abstract: SUMMARY The intracellular O-linked N-acetylglucosamine (O-GlcNAc) glycosylation mediates many signal transduction events and regulates tumorigenesis. Previously the RNA N6-methyladenosine (m 6 A) 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 are 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.
Source: Fundamental Research
Authors: Jie Li, Jie Li, Wen Zhou, Jianzhi Zhang, Li Ma, Zhuan Lv, Yiqun Geng, Xing Chen, Jing Li, Jing Li
Institutions: Capital Normal University, Peking University, Beijing National Laboratory for Molecular Sciences, Center for Life Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education, Peking University Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4401014965