ETS1 Promotes Aerobic Glycolysis and Growth in Head and Neck Squamous Cell Carcinoma by Targeting RRAS2

Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy with a five-year survival rate below 50%, highlighting the urgent need for novel therapeutic targets. This study explores the role of the small GTPase RRAS2 in HNSCC progression and its regulation of glycolysis. Analysis of data from the TCGA and GTEx databases revealed that RRAS2 is significantly upregulated in HNSCC tissues and is associated with poorer overall patient survival. Functional experiments demonstrated that silencing RRAS2 in HNSCC cell lines inhibits glycolytic activity and cell proliferation while promoting apoptosis, whereas overexpression of RRAS2 enhances glycolysis and cell growth. Additionally, bioinformatics and experimental approaches identified the transcription factor ETS1 as an upstream regulator of RRAS2. ETS1 binds to the RRAS2 promoter, facilitating its transcription and contributing to metabolic reprogramming in HNSCC cells. Rescue experiments confirmed that the ETS1-RRAS2 axis is crucial for maintaining the glycolytic phenotype and proliferative capacity of HNSCC cells. These findings suggest that the ETS1-RRAS2 pathway plays a critical role in HNSCC progression and metabolic adaptation, positioning RRAS2 as a potential therapeutic target for improving patient outcomes.