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 can promote development of tumors. 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, the first identified m6A demethylase that has been shown to be upregulated in various cancers.
A research team at the University of Chicago, conducted a study to identify candidates capable of degrading this protein. FTO drew attention in the field of obesity even before its role in RNA modification was fully understood. Earlier in 2019 scientist observed elevated levels of FTO in melanoma and environmental factors like arsenic and UV radiation elevate FTO levels, leading to reduced RNA modifications in melanoma and other cancers. While several small molecule FTO inhibitors have been identified, their clinical usefulness was limited due to their unknown or undesirable toxicity profiles. The team screened multiple compounds and discovered vitamin E succinate as a potential degrader of FTO. 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.
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”. 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. 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.
Basically, this investigation identified a dietary degrader for FTO that inhibits tumor growth and overcomes immunotherapy resistance. Unlike some of the other small inhibitors, VES has a well-characterized safety profile and is widely used as a dietary supplement. This opens the possibility to employ a molecule not absolutely needing any kind of large investigational studies.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Cui YH, Wei J et al. PNAS USA. 2024; 121(51):e2407910121.
Ruan DY, Li T et al. Oncogene. 2021 Aug; 40(33):5168-5181.
Barbieri I, Kouzarides T. Nature Rev Cancer 2017; 20:303-22.
