According to a recent study published on Oncogenesis, a team led by Prof. FANG Zhiyou and Pro. CHEN Xueran from the Hefei Institutes of Physical Science (HFIPS) of the Chinese Academy of Sciences (CAS) found, for the first time, that palmitoylation regulated the activity of glycogen synthase kinase 3β (GSK3β), activating the EZH2–STAT3 pathway and promoting glioblastoma (GBM) temozolomide (TMZ) resistance and glioblastoma stem cells (GSC) self-renewal.

Due to the blood-brain barrier, TMZ is currently the most commonly used chemotherapeutic drug for the clinical treatment of GBM. However, the mechanism of TMZ resistance is not completely clear. Recent data have implicated the involvement of protein palmitoylation dysfunctions in GBM progression and chemotherapy resistance in some tumor types. Therefore, palmitoylation is a valuable research direction to address TMZ resistance.

In this study, scientists discovered novel mechanistic evidence relating signaling pathways with GSC in GBM. They also investigated the role of palmitoyltransferase ZDHHC4 in activating GSK3β and its target, EZH2/STAT3 in GSC self-renewal.

As a result, ZDHHC4-GSK3β-STAT3 axis, which was involved in TMZ resistance in GBM, was identified. They found that phosphorylation of EZH2/STAT3 signaling was downregulated by reducing ZDHHC4 expression or GSK3β palmitoylation, thereby inhibiting GSC self-renewal, TMZ chemotherapy resistance, and tumorigenesis.

"This study," said ZHAO Chenggang, who conducted the research, "identified ZDHHC4 as a potential GBM diagnostic marker and drug target, deepened the understanding of GBM chemotherapy resistance and paved the way for targeted therapies for GBM."

This research was supported by the National Natural Science Foundation of China, the Youth Innovation Promotion Association of CAS, the Innovative Program of Development Foundation of Hefei Centre for Physical Science and Technology and the National Key R&D Program of China.

Schematic illustration of the mechanism of ZDHHC4-mediated GSK3β palmitoylation promotes GBM TMZ-resistance. (Image by Zhao Chenggang)