Yin Narui, Xie Ting, Zhang Haowen, Chen Jian, Yu Jiahua, Liu Fenju
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
Department of Radiobiology, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Suzhou, Jiangsu 215123, P.R. China.
Oncol Lett. 2020 Feb;19(2):1322-1330. doi: 10.3892/ol.2019.11148. Epub 2019 Nov 25.
Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated gene in World Health Organization grade II-III and secondary glioma. The majority of IDH1 mutation cases involve the substitution from arginine to histidine at codon 132 (IDH1-R132H). Although the oncogenic role of IDH1-R132H has been confirmed, patients with IDH1-R132H brain tumors exhibit a better response to radiotherapy compared with those with wild-type (WT) IDH1. In the present study, the potential mechanism of radiosensitization mediated by IDH1-R132H was investigated by overexpressing IDH1-R132H in U87MG glioma cells. The results demonstrated decreased clonogenic capacity of IDH1-R132H-expressing cells, as well as delayed repair of DNA double-strand breaks compared with IDH1-WT. Data from The Cancer Genome Atlas were analyzed, which demonstrated that the expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) was lower in patients with glioma harboring IDH1 mutations compared with that in patients with IDH1-WT. TIGAR-knockdown increases the radiosensitivity of glioma cells; in U87MG cells, IDH1-R132H suppressed TIGAR expression. Chromatin immunoprecipitation assays revealed increased levels of repressive H3K9me3 markers at the TIGAR promoter in IDH1-R132H compared with IDH1-WT. These data indicated that IDH1-R132H may overcome radioresistance in glioma cells through epigenetic suppression of TIGAR expression. However, these favorable effects were not observed in U87MG glioma stem-like cells. The results of the present study provide an improved understanding of the functionality of IDH1 mutations in glioma cells, which may improve the therapeutic efficacy of radiotherapy.
异柠檬酸脱氢酶1（IDH1）是世界卫生组织II - III级和继发性胶质瘤中最常发生突变的基因。大多数IDH1突变病例涉及密码子132处的精氨酸被组氨酸取代（IDH1-R132H）。尽管IDH1-R132H的致癌作用已得到证实，但与野生型（WT）IDH1的患者相比，IDH1-R132H脑肿瘤患者对放疗表现出更好的反应。在本研究中，通过在U87MG胶质瘤细胞中过表达IDH1-R132H来研究IDH1-R132H介导的放射增敏的潜在机制。结果表明，与IDH1-WT相比，表达IDH1-R132H的细胞克隆形成能力下降，并且DNA双链断裂的修复延迟。分析了来自癌症基因组图谱的数据，结果表明，与IDH1-WT的患者相比，携带IDH1突变的胶质瘤患者中TP53诱导的糖酵解和凋亡调节因子（TIGAR）的表达较低。敲低TIGAR可增加胶质瘤细胞的放射敏感性；在U87MG细胞中，IDH1-R132H抑制TIGAR表达。染色质免疫沉淀分析显示，与IDH1-WT相比，IDH1-R132H的TIGAR启动子处抑制性H3K9me3标记物水平增加。这些数据表明，IDH1-R132H可能通过表观遗传抑制TIGAR表达来克服胶质瘤细胞的放射抗性。然而，在U87MG胶质瘤干细胞样细胞中未观察到这些有利作用。本研究结果有助于更好地理解IDH1突变在胶质瘤细胞中的功能，这可能提高放疗的治疗效果。
