High levels of fat mass and obesity-associated protein (FTO) have been linked to increased tumor growth and resistance to immunotherapy. In a study recently published in PNAS , researchers from the University of Chicago Medicine identified vitamin E succinate (VES) as an effective agent in controlling tumor growth by promoting the degradation of FTO.
Epigenetics and epitranscriptomics play a crucial role in modifying gene expression without altering gene sequence. N6-methyladenosine (m6A) is one such mechanism, where methyl groups are added to the N6 position of adenosine on RNA. Adding these methyl groups enhances RNA stability; however, their removal by enzymes such as FTO can promote development of tumors.
FTO was the first identified m6A demethylase and has been shown to be upregulated in various cancers. A research team led by Yu-Ying He, PhD , Professor of Medicine in the Section of Dermatology at the University of Chicago, conducted a study to identify candidates capable of degrading FTO.
FTO drew attention in the field of obesity even before its role in RNA modification was fully understood.
"In our earlier studies published in 2019 , we observed elevated levels of FTO in melanoma, a type of skin cancer. We identified environmental factors such as UV radiation and arsenic exposure that elevate FTO levels, leading to reduced RNA modifications in melanoma and other cancers," Yu-Ying He said.
While several small molecule FTO inhibitors have been identified, their clinical usefulness was limited due to their unknown or undesirable toxicity profiles.
In collaboration with Chuan He, PhD , John T. Wilson Distinguished Service Professor of Chemistry at the University of Chicago and a pioneer in the field of epigenetics and epitranscriptomics, Yu-Ying He's team screened multiple compounds and discovered vitamin E succinate as a potential degrader of FTO.
"Unlike some of the other small inhibitors, VES has a well-characterized safety profile and is widely used as a dietary supplement," said Yu-Ying He.
Using molecular docking tools, researchers confirmed that VES binds effectively to FTO, leading to its degradation, while other vitamins or vitamin E derivatives did not show the same effect. Since the degradation of most proteins is mediated by E3 ubiquitin ligases, the team further investigated and identified DTX2 as the E3 ubiquitin ligase involved in VES-mediated FTO degradation.
"Vitamin E succinate consists of two parts: succinate, which binds to FTO, and vitamin E, which binds to DTX2, the E3 ligase. This dual interaction brings DTX2 and FTO together, facilitating FTO degradation, essentially acting like a molecular glue," said Yu-Ying He.
To explore how VES suppresses tumorigenesis and enhances tumor sensitivity to immunotherapy, the researchers conducted experiments that ultimately demonstrated that VES enhances T-cell mediated cytotoxicity through tumor-intrinsic FTO suppression.
"As a widely used dietary supplement with a known safety profile, VES holds potential as a therapeutic strategy for cancers resistant to immunotherapy and characterized by high FTO levels," said Yu-Ying He.
The study, " Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity ," was published in December 2024 and was supported by the National Institutes of Health, the University of Chicago Medicine Comprehensive Cancer Center, and the University of Chicago Friends of Dermatology Endowment Fund.
Additional authors include Yan-Hong Cui, Jiangbo Wei, Hao Fan, Wenlong Li, Lijie Zhao, Emma Wilkinson, Jack Peterson, Lishi Xie, Zhongyu Zou, Seungwon Yang, Mark Applebaum, Justin Kline, and Jing Chen from the University of Chicago.
