Centers and Institutes
Published December 11, 2024 | Version v1
Journal article Open

Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity

Creators

  • 1. University of Chicago

Description

Here, we show that vitamin E succinate (VES) acts as a degrader for the m6A RNA demethylase fat mass and obesity-associated protein (FTO), thus suppressing tumor growth and resistance to immunotherapy. FTO is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and subsequent degradation in the proteasome. VES binds to FTO and DTX2, leading to enhanced FTO–DTX2 interaction, FTO ubiquitination, and degradation in FTO-dependent tumor cells. VES suppressed tumor growth and enhanced antitumor immunity and response to immunotherapy in vivo in mouse models. Genetic FTO knockdown or VES treatment increased m6A methylation in the LIF (Leukemia Inhibitory Factor) gene and decreased LIF mRNA decay, and thus sensitized melanoma cells to T cell–mediated cytotoxicity. Taken together, our findings reveal the underlying molecular mechanism for FTO protein degradation and identify a dietary degrader for FTO that inhibits tumor growth and overcomes immunotherapy resistance.

Data availability

RNA seq data have been deposited in GEO [RNA sequencing data are accessible at the GEO repository, under accession number GSE250332 (67). All the software and packages used in this article are publicly available.

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cui-et-al-2024-targeting-dtx2-ufd1-mediated-fto-degradation-to-regulate-antitumor-immunity.pdf

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Additional details

Identifiers

DOI
10.1073/pnas.2407910121
Other
oai:uchicago.tind.io:14247

Funding

Human Tissue Resource Center
SCR_019199
Cytometry and Antibody Technology
SCR_017760
National Institutes of Health
ES031693
National Institutes of Health
ES031534
University of Chicago
CA014599
CACHET
ES027792
University of Chicago
Friends of Dermatology Endowment Fund

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Biochemistry and Molecular Biology, Chemistry, Medicine, Pediatrics
Center(s) or Institute(s)
Institute for Biophysical Dynamics