SETD2 Palmitoylation Mediated by ZDHHC16 in Epidermal Growth Factor Receptor-Mutated Glioblastoma Promotes Ionizing Radiation-Induced DNA Damage.

Xiaoqing Fan, Suling Sun, Haoran Yang, Huihui Ma, Chenggang Zhao, Wanxiang Niu, Junqi Fan, Zhiyou Fang, Xueran Chen

International journal of radiation oncology, biology, physics 2022 Jul 01

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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. Bioinformatics analysis, western blotting, immunofluorescence, and immunohistochemistry 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 (pharmacologic treatment, flow cytometry, transwell migration assay, and coimmunoprecipitation) and in vivo (xenograft model) experiments. 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 suggest that a depalmitoylation inhibitor, PalmB, is useful as a potentially novel adjuvant treatment for patients with GBM undergoing radiation therapy. Our data present novel mechanistic evidence relating to signaling pathways with DNA damage responses in EGFR-mutated GBM. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Xiaoqing Fan, Suling Sun, Haoran Yang, Huihui Ma, Chenggang Zhao, Wanxiang Niu, Junqi Fan, Zhiyou Fang, Xueran Chen. SETD2 Palmitoylation Mediated by ZDHHC16 in Epidermal Growth Factor Receptor-Mutated Glioblastoma Promotes Ionizing Radiation-Induced DNA Damage. International journal of radiation oncology, biology, physics. 2022 Jul 01;113(3):648-660