Transcriptional regulation of UGT8 by ELF4 drives esophageal squamous cell carcinoma progression

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Abstract Background Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of esophageal cancers in China and is associated with poor prognosis. Insensitivity to cisplatin (CDDP) poses a major challenge for ESCC treatment. UDP-glycosyltransferase 8 (UGT8), the sole enzyme responsible for catalyzing the conversion of ceramide to galactosylceramide (GalCer), regulates sphingolipid metabolism; however, its role in ESCC remains unclear. Methods UGT8 expression and clinical relevance were analyzed using public databases, patient tumor samples, and tissue microarrays. Functional assays were conducted to assess the effects of UGT8 on ESCC cell proliferation, migration, invasion, and apoptosis in vitro, as well as tumor growth and metastasis in vivo. ChIP assays were performed to evaluate ELF4-mediated transcriptional regulation of UGT8. ELISA assays were used to quantify cellular ceramide levels. Flow cytometry was performed to measure apoptosis and surface GalCer expression. The therapeutic efficacy of UGT8 inhibition, alone or in combination with CDDP, was evaluated in preclinical models. Results UGT8 was significantly upregulated in ESCC and correlated with advanced tumor stage, metastasis, and poor patient survival. UGT8 promoted malignant phenotypes while suppressing apoptosis. Genetic or pharmacological inhibition of UGT8 disrupted sphingolipid homeostasis, characterized by increased ceramide accumulation and reduced GalCer production, leading to enhanced apoptosis and suppressed tumor growth. Importantly, pharmacological targeting of UGT8 with UGT8-IN-1 enhanced the antitumor activity of CDDP in preclinical models. Mechanistically, ELF4 directly transcriptionally activated UGT8 to promote ceramide metabolic remodeling. Conclusions UGT8 is transcriptionally activated by ELF4 and plays a critical role in driving ESCC progression. Targeting UGT8 may represent a promising translational strategy to sensitize ESCC to chemotherapy and improve therapeutic outcomes.