GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2-STAT3 axis

Glioblastoma stem cells (GSCs) are a highly tumorigenic cell subgroup of glioblastoma (GBM). Glycogen synthase kinase 3 beta (GSK3 beta) is considered a key hub for promoting malignant phenotypes in GBM. However, the functional relationships between GSK3 beta and GSCs in GBM are unclear. Here, we found that GSK3 beta was noted as a substrate for ZDHHC4-mediated palmitoylation at the Cys14 residue, which enhanced GBM temozolomide (TMZ) resistance and GSC self-renewal. Clinically, the expression level of ZDHHC4 was upregulated in GBM, which significantly correlated with tumor grade and poor prognosis. The above phenotypes were based on decreasing p-Ser9 and increasing p-Tyr216 by GSK3 beta palmitoylation, which further activated the enhancer of the zeste homolog 2 (EZH2)-STAT3 pathway. Notably, STAT3 silencing also inhibited ZDHHC4 expression. This study revealed that GSK3 beta palmitoylation mediated by ZDHHC4 improved the stemness of TMZ-resistant GBM by activating the EZH2-STAT3 signaling axis, providing a new theoretical basis for further understanding the mechanism of TMZ resistance and recurrence after treatment.

Automated summary

This study revealed the role of GSK3β in temozolomide resistance in GBM, showing that palmitoylation mediated by ZDHHC4 enhances stemness and activates the EZH2-STAT3 pathway.