据报道，胶质母细胞瘤干细胞（GSC）会导致治疗耐药，从而导致胶质母细胞瘤预后不良。 γ-谷氨酰环转移酶 (GGCT) 在包括胶质母细胞瘤在内的多种癌症类型中高度表达，其抑制作用可抑制癌细胞生长。然而，GGCT过表达的机制及其在GSC中的功能尚不清楚。在这项研究中，我们发现 GGCT 在小鼠胶质母细胞瘤模型建立的 GSC 中高表达，并且其敲低可抑制其增殖。分析NRas及其下游转录因子c-Jun对GGCT表达的影响； NRas 敲低降低了 c-Jun 和 GGCT 表达。 c-Jun 的敲低也降低了 GGCT 的表达水平并抑制细胞增殖。与此一致的是，用 SP600125 对 c-Jun 进行药理抑制可降低 GGCT 并抑制 GSC 增殖。此外，GGCT启动子-报告基因突变分析表明，c-Jun通过AP-1共有序列调节GGCT启动子的活性。基因表达分析显示，GGCT 敲低对 Delta-Notch 通路表现出抑制作用，并降低了 Notch1 的表达。仅敲除 Notch1 即可抑制 GSC 增殖，证实 Notch1 在该模型中具有功能。 Notch1胞内结构域的强制表达恢复了GGCT敲低的生长抑制作用。此外，GGCT 敲低抑制了 GSC 体内致瘤潜力。这些结果表明，c-Jun促进表达的GGCT在GSC的增殖和致瘤潜力中发挥着重要作用，并且其敲低引起的表型是由Notch1的减少造成的。因此，GGCT 可能代表攻击 GSC 的新治疗靶点。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Glioblastoma stem cells (GSCs) have been reported to cause poor prognosis of glioblastoma by contributing to therapy resistance. γ-Glutamylcyclotransferase (GGCT) is highly expressed in various cancer types, including glioblastoma, and its inhibition suppresses cancer cell growth. However, the mechanism of GGCT overexpression and its function in GSCs are unknown. In this study, we show that GGCT is highly expressed in GSCs established from a mouse glioblastoma model and its knockdown suppresses their proliferation. Effects of NRas and its downstream transcription factor c-Jun on GGCT expression were analyzed; NRas knockdown reduced c-Jun and GGCT expression. Knockdown of c-Jun also reduced expression levels of GGCT and inhibited cell proliferation. Consistent with this, pharmacological inhibition of c-Jun with SP600125 reduced GGCT and inhibited GSC proliferation. Furthermore, the GGCT promoter-reporter assay with mutagenesis demonstrated that c-Jun regulates the activity of the GGCT promoter via AP-1 consensus sequence. Gene expression analysis revealed that GGCT knockdown showed a repressive effect on the Delta-Notch pathway and decreased Notch1 expression. Notch1 knockdown alone inhibited the GSC proliferation, confirming that Notch1 is functional in this model. Forced expression of the Notch1 intracellular domain restored the growth inhibitory effect of GGCT knockdown. Moreover, GGCT knockdown inhibited GSC tumorigenic potential in vivo. These results indicate that GGCT, whose expression is promoted by c-Jun, plays an important role in the proliferation and tumorigenic potential of GSCs, and that the phenotype caused by its knockdown is contributed by a decrease in Notch1. Thus, GGCT may represent a novel therapeutic target for attacking GSCs.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.