Gu Xiao, He Miao, Lebedev Timofey, Lin Cheng-Han, Hua Zhong-Yan, Zheng Y George, Li Zhi-Jie, Yang Jer-Yen, Li Xing-Guo
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China.
Biochem Biophys Rep. 2022 Oct 6;32:101364. doi: 10.1016/j.bbrep.2022.101364. eCollection 2022 Dec.
Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of brain tumors, but the role of PRMT1 in medulloblastoma, the most common malignant pediatric brain tumor, remains unexplored By examining the publicly available databases of pediatric brain tumor collection, we found that PRMT1 was predominantly expressed in medulloblastomas across all the pediatric brain tumors and that the high-level expression of PRMT1 correlated with poor survival of medulloblastoma patients. To determine the role of PRMT1 in medulloblastoma cells, we established an inducible knockdown system and demonstrated that PRMT1 depletion decreased medulloblastoma cell proliferation and induced cell apoptosis. Furthermore, the diamidine compounds, previously shown to exhibit selective PRMT1 inhibition, suppressed medulloblastoma cell viability in a dose-dependent manner. Finally, we observed induction of medulloblastoma cell apoptosis by the potent diamidine compounds at low micromolar concentrations. Together, our results suggest that PRMT1 could be an actionable therapeutic target in medulloblastoma.
蛋白质精氨酸甲基转移酶(PRMTs)的异常表达与多种脑肿瘤有关,但PRMT1在髓母细胞瘤(最常见的儿童恶性脑肿瘤)中的作用仍未得到探索。通过检查公开可用的儿童脑肿瘤收集数据库,我们发现PRMT1在所有儿童脑肿瘤中的髓母细胞瘤中主要表达,并且PRMT1的高水平表达与髓母细胞瘤患者的不良生存相关。为了确定PRMT1在髓母细胞瘤细胞中的作用,我们建立了一个可诱导的敲低系统,并证明PRMT1的缺失会降低髓母细胞瘤细胞的增殖并诱导细胞凋亡。此外,先前显示具有选择性PRMT1抑制作用的脒化合物以剂量依赖性方式抑制髓母细胞瘤细胞活力。最后,我们观察到低微摩尔浓度的强效脒化合物可诱导髓母细胞瘤细胞凋亡。总之,我们的结果表明PRMT1可能是髓母细胞瘤中一个可行的治疗靶点。