The dysregulation of UPP1 incurred by METTL3 regulates the malignancy of esophageal squamous cell carcinoma in an m6A-YTHDC1-KLF5-mediated manner

Uridine Phosphorylase 1 (UPP1) has been shown to catalyze the generation of ribose derived from uridine, to promote central carbon metabolism, and to collaborate with glucose to drive aerobic glycolysis in tumor cells, thereby playing an oncogenic role in several cancers. However, its correlation with the onset and progression of esophageal squamous cell carcinoma (ESCC) has not been explored. We revealed that UPP1 was highly expressed in ESCC, and that loss of UPP1 impaired the malignancy of ESCC cells in vitro and in vivo. We found that silencing methyltransferase-like 3 (METTL3) reduced m⁶A modification in the 3'-untranslated regions (3'UTR) of Krüppel-like factor 5 (KLF5), which decreased its interaction with YTH N6-Methyladenosine RNA Binding Protein C1 (YTHDC1), and subsequently upregulated the expression of KLF5 by reducing its precursor mRNA (pre-mRNA) levels in ESCC cells. Further study revealed that KLF5 negatively regulated the expression of UPP1 through transcriptional modulation. Our findings establish that the dysregulation of UPP1 in ESCC is modulated by METTL3 in an m⁶A-YTHDC1-KLF5-mediated manner, indicating a potential therapeutic target for ESCC.

Esophageal squamous cell carcinoma; Krüppel-like factor 5; Methyltransferase-like 3; Uridine phosphorylase 1; YTH N6-Methyladenosine RNA Binding Protein C1.