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

Abstract

SUMMARYThe 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 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.

Understanding the redundant functions of the m6A-binding YTHDF proteins

“…One such mechanism might be glycosylation. Recent studies have highlighted that YTHDF1, YTHDF2, and YTHDF3 are glycosylated, which affects their binding partners, although the levels of glycosylation for each paralog appear to differ based on cell type ( Chen et al 2023 ; Li et al 2023 ). The ability of the YTHDF proteins to be differentially regulated can allow one paralog to be more effective at mediating mRNA degradation in some cellular contexts, thus fine-tuning YTHDF-dependent m 6 A-mRNA degradation.…”