Interference with ENO2 promotes ferroptosis and inhibits glycolysis in clear cell renal cell carcinoma by regulating Hippo‑YAP1 signaling

Glycolytic enzyme Enolase 2 (ENO2) is dysregulated in various Cancer types. Nevertheless, the role and underlying mechanism of ENO2 in clear cell renal cell carcinoma (ccRCC) remain unclear. Therefore, the current study investigated the effect and mechanism of ENO2 in ccRCC. ENO2 expression in a ccRCC cell line was assessed using reverse transcription-quantitative PCR and western blotting. Analysis of glycolysis was performed by estimating the extracellular acidification rate, lactic acid concentration, glucose uptake and the expression of glucose transporter 1, Pyruvate Kinase muscle isozyme M2 and Hexokinase 2. Moreover, Ferroptosis was assessed by detecting the level of total iron, lipid peroxide, Reactive Oxygen Species and the expression of ferroptosis-related protein. In addition, mitochondrial function was assessed using JC-1 staining and detection kits. The results indicated that ENO2 is expressed at high levels in ccRCC cell lines, and interference with ENO2 expression inhibits glycolysis, promotes Ferroptosis and affects mitochondrial function in ccRCC cells. Further investigation demonstrated that interference with ENO2 expression affected Ferroptosis levels in ccRCC cells by inhibiting the glycolysis process. Mechanistically, the present results indicated that ENO2 may affect Ferroptosis, glycolysis and mitochondrial functions by regulating Hippo-yes-associated protein 1 (YAP1) signaling in ccRCC cells. In conclusion, the present study showed that ENO2 affects Ferroptosis, glycolysis and mitochondrial functions in ccRCC cells by regulating Hippo-YAP1 signaling, hence demonstrating its potential as a therapeutic target in ccRCC.

Hippo-YAP1 signaling; clear cell renal cell carcinoma; enolase 2; ferroptosis; glycolysis; mitochondrial function.