Regulation of RNA methylation by therapy treatment, promotes tumor survival.

Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival. m6A enzyme translation upon therapy stress, promotes tumor survival.

Citation

Syed Ia Bukhari, Samuel S Truesdell, Chandreyee Datta, Pritha Choudhury, Keith Q Wu, Jitendra Shrestha, Ruby Maharjan, Ethan Plotsker, Ramzi Elased, Sadia Laisa, Vijeta Bhambhani, Yue Lin, Johannes Kreuzer, Robert Morris, Siang-Boon Koh, Leif W Ellisen, Wilhelm Haas, Amy Ly, Shobha Vasudevan. Regulation of RNA methylation by therapy treatment, promotes tumor survival. bioRxiv : the preprint server for biology. 2023 May 20

PMID: 37292633

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