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

Here, we show that vitamin E succinate (VES) acts as a degrader for the m<sup>6</sup>A 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 m<sup>6</sup>A 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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-12-11
DOI
https://doi.org/10.1073/pnas.2407910121
Citations
6
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
1.40

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article

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

Seungwon Yang, Justin Paul Kline, Yu‐Ying He, Yan‐Hong Cui et al.
6 citations
Proceedings of the National Academy of Sciences
RNA modifications and cancer
1.40
article

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

Seungwon Yang, Justin Paul Kline, Yu‐Ying He, Yan‐Hong Cui, Jiangbo Wei, Lishi Xie, Emma Wilkinson, Hao Fan, Mark A. Applebaum, Zhongyu Zou, Chuan He, Jing Chen, Wenlong Li, Zhao Li-jie, Jack Peterson
article en
6 citations

Abstract

Here, we show that vitamin E succinate (VES) acts as a degrader for the m<sup>6</sup>A 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 m<sup>6</sup>A 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.

Proceedings of the National Academy of SciencesVol. 121(51)
University of Chicago (US)
Howard Hughes Medical Institute, National Institutes of Health, Hospitality and Tourism Research Centre, Hong Kong Polytechnic University, National Institute of Environmental Health Sciences
Good health and well-being
Openalex Percentile: Top 18%
RNA modifications and cancer
1.40
DOIOpen Access PDFOpenAlex
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