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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• The fat mass and obesity-associated protein (FTO) is an m⁶A RNA demethylase implicated in tumor growth and immunotherapy resistance.
• Understanding FTO's regulatory mechanisms is crucial for developing novel cancer therapies.

Purpose of the Study:

• To investigate the role of vitamin E succinate (VES) in regulating FTO protein levels.
• To elucidate the molecular mechanism by which VES affects FTO.
• To evaluate the therapeutic potential of VES in suppressing tumor growth and overcoming immunotherapy resistance.

Main Methods:

• Investigated the interaction between VES, FTO, and its E3 ligase DTX2.
• Assessed FTO ubiquitination and proteasomal degradation.
• Utilized mouse models to evaluate tumor growth and immunotherapy response.
• Analyzed m⁶A methylation levels and mRNA decay of Leukemia Inhibitory Factor (LIF).

Main Results:

• VES enhances the interaction between FTO and DTX2, promoting FTO ubiquitination and degradation.
• VES treatment suppressed tumor growth and improved antitumor immunity and immunotherapy response in vivo.
• FTO knockdown or VES treatment increased m⁶A methylation of LIF and decreased its mRNA decay.
• Melanoma cells were sensitized to T cell-mediated cytotoxicity.

Conclusions:

• Vitamin E succinate (VES) acts as a dietary degrader of the FTO protein.
• VES inhibits tumor growth and overcomes immunotherapy resistance by promoting FTO degradation.
• This study identifies a novel therapeutic strategy targeting FTO for cancer treatment.