Department of Neurosurgery, Graduate School of Medicine, Kyoto University; Kyoto City, Kyoto, 606-8507, Japan.
Department of Human Health Sciences, Graduate School of Medicine, Kyoto University; Kyoto City, Kyoto, 606-8507, Japan.
Commun Biol. 2022 Sep 9;5(1):939. doi: 10.1038/s42003-022-03917-5.
Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma.
胶质母细胞瘤是最常见的成人脑肿瘤，具有高度恶性。转录因子如 RUNX1 被认为参与了胶质母细胞瘤的恶性转化。RUNX1 作为癌基因或肿瘤抑制基因，具有多种靶基因。RUNX1 对胶质母细胞瘤获得恶性的影响的细节尚不清楚。在这里，我们表明 RUNX1 通过增强 BIRC5 和 PIF1 的表达来下调 p21，赋予胶质母细胞瘤抗凋亡特性。使用设计为适合 RUNX1 DNA 沟的烷基化剂偶联的吡咯-咪唑聚酰胺进行基因开关关闭治疗，降低了 BIRC5 和 PIF1 的表达水平，并通过 p21 诱导细胞凋亡和细胞周期停滞。RUNX1-BIRC5/PIF1-p21 通路似乎反映了胶质母细胞瘤的难治性特征，因此有望成为治疗靶点。RUNX 基因开关关闭治疗可能代表胶质母细胞瘤的一种新的治疗方法。
