Faculty, Staff and Student Publications
Publication Date
5-2-2024
Journal
Molecular Cell
Abstract
eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.
Keywords
Humans, Animals, Methylation, Lung Neoplasms, Peptide Elongation Factor 2, Adenocarcinoma of Lung, Mice, RNA, Messenger, Carcinogenesis, Cell Proliferation, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Peptide Chain Elongation, Translational, Mice, Nude, Protein Processing, Post-Translational, Female, FAM86A, KRAS, cancer, eEF2, elongation, lung, lysine methylation, mRNA translation, protein synthesis.
DOI
10.1016/j.molcel.2024.02.037
PMID
38508183
PMCID
PMC11069438
PubMedCentral® Posted Date
5-2-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
no
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