SEDT2 palmitoylation mediated by ZDHHC16 in EGFR-mutated glioblastoma promotes ionizing radiation-induced DNA damage

Abstract

Purpose: The prevalence of epidermal growth factor receptor (EGFR) mutations in glioblastoma multiforme (GBM) has elicited a significant focus on EGFR as a potential drug target. However, no significant clinical advancement in GBM treatment has occurred. Methods and Materials: Bioinformatics analysis, western blotting, immunofluorescence, and immunohistochemistry (IHC) were performed to detect the expression of ZDHHC16 and genetic EGFR alterations in GBM. The biological function of ZDHHC16/SETD2/H3K36me3 signaling axis after EGFR alterations was demonstrated by various in vitro (pharmacological treatment, flow cytometry, transwell migration assay, and coimmunoprecipitation) and in vivo (xenograft model) experiments. Results: We demonstrate that the ZDHHC16/SETD2/H3K36me3 signaling axis was inactivated in EGFR-altered GBM. ZDHHC16 was downregulated in GBM versus normal brain tissue; this was significantly related to EGFR alterations. These events contributed to p53 activation, halting cells at the G1/S checkpoint. Furthermore, DNA damage repair signaling in EGFR-amplified GBMs was affected after ionizing radiation-induced DNA damage via reduced SETD2 palmitoylation and methylation of its target, H3K36. Our findings suggested that a depalmitoylation inhibitor, PalmB, is useful as a potentially novel adjuvant treatment for patients with GBM undergoing radiotherapy. Conclusions: Our data present novel mechanistic evidence relating to signaling pathways with DNA damage responses in EGFR-mutated GBM.