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• W4380082704 abstract "Introduction: N6-methyladenosine (m6A) is the most abundant modification in eukaryotes and plays an important biological function in human diseases. YTHDF2 is an important m6A reading protein, which could specifically bind to m6A-modified RNA and mediate its degradation. Here, we explored the functional significance and regulatory mechanism of YTHDF2 in diffuse large B-cell lymphoma (DLBCL), expecting to propose a novel therapeutic strategy. Methods: Lymph node biopsies from 120 de novo DLBCL patients and 20 reactive hyperplasia cases were collected with informed consent. The biological function of YTHDF2 was evaluated via constructing YTHDF2 stable knockdown and overexpression models and CRISPR/Cas9 mediated genomic deletion. RNA-seq and lipidomic sequencing were conducted to detect the dysregulated RNA in YTHDF2-knockout DLBCL cells. MeRIP-seq, m6A methylation assays and dual-luciferase reporter assay were performed to explore the functional mechanism of YTHDF2. Xenograft DLBCL mice model was simultaneously established. Animal experiments were performed in accordance with the principles of the Institutional Animal Care. Results: The upregulation of YTHDF2 mRNA and protein in DLBCL cells was found, and high YTHDF2 expression was associated with aggressive disease process. Knockdown of YTHDF2 impaired cell proliferation, induced cell cycle arrest and triggered cell apoptosis in vitro, and repressed tumor growth in vivo. Furthermore, By RNA-seq, lipidomics, and MeRIP-seq analysis, YTHDF2 was found to regulate ceramide metabolism in DLBCL cells. The exogenous ceramide treatment suppressed tumor growth in DLBCL cells. YTHDF2 bound to ACER2 mRNA at m6A sites, promoting the expression and stability of ACER2. As ACER2 expression was enhanced, ceramides were hydrolyzed, disrupting ceramide and sphingosine-1-phosphate (S1P) balances, activating ERK and PI3K/AKT pathways, and promoting DLBCL tumorigenesis (Figure 1). Conclusions: Our present study provides in vitro and in vivo evidence for the significance of YTHDF2 in lymphomagenesis and highlights the regulatory mechanism of YTHDF2 on ACER2-ceramide metabolic axis in DLBCL. Further investigations on the specific inhibitors of YTHDF2 in DLBCL will outline a promising therapeutic option in DLBCL therapy. Keywords: aggressive B-cell non-Hodgkin lymphoma, genomics, epigenomics, and other -omics, molecular targeted therapies No conflicts of interests pertinent to the abstract." @default.
• W4380082704 created "2023-06-10" @default.
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• W4380082704 date "2023-06-01" @default.
• W4380082704 modified "2023-10-13" @default.
• W4380082704 title "THE RNA M6A READER YTHDF2 REGULATES ACER2‐CERAMIDE METABOLIC AXIS TO PROMOTE TUMORIGENESIS OF DIFFUSE LARGE B‐CELL LYMPHOMA" @default.
• W4380082704 doi "https://doi.org/10.1002/hon.3165_471" @default.
• W4380082704 hasPublicationYear "2023" @default.
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