Alteration of Flavin Homeostasis in Uterine Cancer

Uterine cancer is the fourth most frequently diagnosed cancer in women, and continues to present significant clinical challenges, particularly in older populations. Tumor progression is tightly linked to metabolic adaptations, and emerging evidence points to an association between dysregulated vitamin B2 (riboflavin, Rf) metabolism and cancer development. Rf is an essential precursor of the flavin cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are critical for cellular energy metabolism and redox balance. The aim of the study was to investigate whether uterine cancer tissues exhibit alterations in the expression of key regulators of flavin homeostasis - riboflavin transporters (RFVT1-3) and FAD synthase (FADS) - and to determine how these changes relate to intracellular flavin levels and to the expression of the FAD-dependent epigenetic enzyme lysine-specific demethylase 1 (LSD1).

Paired samples of tumor tissue and surrounding normal mucosa from eight patients with uterine cancer were analyzed to evaluate the expression of: RFVTs by both RT-PCR and western blot; and FADS, and the FAD dependent enzyme lysine specific demethylase 1 (LSD1) by RT-PCR. Furthermore, we evaluated flavin cofactors levels by HPLC.

Quantitative analyses revealed a significant up-regulation of RFVT1 and RFVT3 at both mRNA and protein levels in tumor tissues, accompanied by markedly increased intracellular levels of Rf (3fold) and FAD (2.5fold). FADS, the enzyme responsible for FAD production and delivery to client flavoproteins, was also significantly overexpressed and correlated with elevated LSD1 expression.

A coordinated mechanism where uterine cancer cells adaptively up-regulate RFVTs, FADS, and LSD1 to meet their metabolic demands was revealed. These results provide insights into the metabolic vulnerabilities of uterine cancer and propose Rf metabolism and flavin-dependent processes as potential therapeutic targets.