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FTO degradation targeting enhances anti-tumor immunity

GSE250332 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2024/11/25 Platform GPL24676
Summary
The m6A RNA demethylase Fat mass and obesity-associated protein (FTO) is aberrantly upregulated in numerous cancers and promotes tumor development and therapeutic resistance. Here, using public datasets and screening, we show that FTO is ubiquitinated at lysine 162 by its E3 ligase DTX2, followed by recognition by UFD1, leading to degradation in the proteasomes. Furthermore, we identified vitamin E succinate (VES) as a natural first-in-class degrader for FTO by binding to FTO and DTX2, thus enhancing FTO-DTX2 interaction, leading to increased FTO ubiquitination and degradation and enhanced anti-tumor immunity and response to immunotherapy. Genetic or pharmacological FTO knockdown by VES increased m6A methylation in the LIF gene and thus decreased LIF mRNA decay, and thus sensitized tumor cells to T cell-mediated cytotoxicity. Taken together, our findings elucidated the underlying molecular mechanism for FTO protein degradation and the first natural FTO degrader that reprograms the anti-tumor immunity.
Published in
Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity
Cui YH, Wei J, Fan H et al. · Proceedings of the National Academy of Sciences of the United States of America 2024 · PMID 39661064 · doi:10.1073/pnas.2407910121
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Direct links to NCBI, no account and no request form: the whole study as GSE250332_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 4 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1053378 and SRA study SRP478273. Searching any of these in the dataset finder brings you back here.

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