FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis.

Autor:	Francis JW; Department of Biology, Stanford University, Stanford, CA 94305, USA., Hausmann S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Ikram S; Department of Biology, Stanford University, Stanford, CA 94305, USA., Yin K; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Mealey-Farr R; Department of Biology, Stanford University, Stanford, CA 94305, USA., Flores NM; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Trinh AT; Department of Biology, Stanford University, Stanford, CA 94305, USA., Chasan T; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Thompson J; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Mazur PK; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: pkmazur@mdanderson.org., Gozani O; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 May 02; Vol. 84 (9), pp. 1753-1763.e7. Date of Electronic Publication: 2024 Mar 19.
DOI:	10.1016/j.molcel.2024.02.037
Abstrakt:	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 KRAS G12C -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. Competing Interests: Declaration of interests O.G. is a co-scientific founder, Board of Director member, and stockholder of EpiCypher, Inc. and Alternative Bio, Inc. and a co-scientific founder, consultant, and stockholder of K36 Therapeutics, Inc. P.K.M. is a scientific founder of Amplified Medicines, Inc. and a consultant and stockholder of Ikena Oncology, Inc. and Alternative Bio, Inc. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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