MARCH3 Inhibits Tumorigenesis and Enhances Paclitaxel Sensitivity in Nasopharyngeal Carcinoma by Ubiquitinating Hexokinase 2

Glycolytic enzyme hexokinase 2 (HK2) plays a crucial role in the development of several human cancers, including nasopharyngeal carcinoma (NPC). This project is designed to explore the role and mechanism of HK2 in NPC progression. HK2 and membrane-associated RING-CH-type finger 3 (MARCH3) mRNA and protein levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell viability, proliferation, migration, invasion, and apoptosis were measured using Cell Counting Kit-8 (CCK-8), Colony formation, wound healing, transwell, and flow cytometry. Glycolysis level was detected via specific kits. The stability of HK2 was assessed by Cycloheximide (CHX) assay. After Ubibrowser online database prediction, the interaction between MARCH3 and HK2 was validated using Co-immunoprecipitation (Co-IP) assay and GST pull-down assay. The effect of MARCH3 on PTX sensitivity of NPC was analyzed using in vivo studies. HK2 level was increased in NPC tissues and cell lines, and MARCH3 expression was decreased. Furthermore, HK2 knockdown repressed NPC cell proliferation, migration, invasion, glycolysis, and improved cell sensitivity to PTX. At the molecular level, MARCH3 could promote HK2 ubiquitination and decrease its stability. In addition, overexpressing MARCH3 increased the PTX sensitivity of NPC in vivo. MARCH3 could block NPC progression and strengthen the sensitivity of NPC cells to PTX, possibly by advancing the ubiquitination degradation of HK2, providing a promising therapeutic target for NPC treatment.