Propofol enhances stem-like properties of glioma via GABAAR‐dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism

Propofol is a commonly used anesthetic. However, its effects on glioma growth and recurrence remain largely unknown. The effect of propofol on glioma growth was demonstrated by a series of in vitro and in vivo experiments (spheroidal formation assay, western blotting, and xenograft model). The acyl-biotin exchange method and liquid chromatography-mass spectrometry assays identified palmitoylation proteins mediated by the domain containing the Asp-His-His-Cys family. Western blotting, co-immunoprecipitation, quantitative real-time polymerase chain reaction, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays were used to explore the mechanisms of the γ-aminobutyric acid receptor (GABAAR)/Src/ZDHHC5/EZH2 signaling axis in the effects of propofol on glioma stem cells (GSCs). We found that treatment with a standard dose of propofol promoted glioma growth in nude mice compared with control or low-dose propofol. Propofol-treated GSCs also led to larger tumor growth in nude mice than did vector-treated tumors. Mechanistically, propofol enhances the stem-like properties of gliomas through GABAAR to increase Src expression, thereby enhancing the palmitoylation of ZDHHC5-mediated EZH2 and Oct4 expression. These results demonstrate that propofol may promote glioma growth through the GABAAR-Src-ZDHHC5-EZH2 mechanism and are helpful in guiding the clinical use of propofol to obtain a better patient prognosis after the surgical resection of tumors.