文章：

γ-谷氨酰环化转移酶受c-Jun转录调控，并通过调控Notch1水平控制胶质母细胞瘤干细胞的增殖

γ-Glutamylcyclotransferase is transcriptionally regulated by c-Jun and controls proliferation of glioblastoma stem cells through Notch1 levels 

原文发布日期：2024-10-11 

英文摘要：

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. 

摘要翻译：

胶质母细胞瘤干细胞（GSCs）被报道通过介导治疗抵抗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表达，抑制该酶可抑制癌细胞生长。然而，GGCT的过表达机制及其在GSCs中的功能尚不明确。本研究表明，在从小鼠胶质母细胞瘤模型建立的GSCs中，GGCT呈高表达状态，敲低该基因可抑制细胞增殖。通过分析NRas及其下游转录因子c-Jun对GGCT表达的影响，发现敲低NRas可降低c-Jun和GGCT的表达水平。c-Jun的敲低同样降低了GGCT表达并抑制细胞增殖。与此一致的是，使用SP600125药物抑制c-Jun后，GGCT表达下降且GSC增殖受抑。进一步通过GGCT启动子报告基因突变实验证实，c-Jun通过AP-1一致性序列调控GGCT启动子活性。基因表达分析显示，GGCT敲低对Delta-Notch通路产生抑制作用并降低Notch1表达。单独敲低Notch1即可抑制GSC增殖，证实Notch1在该模型中具有功能活性。强制表达Notch1胞内结构域可逆转GGCT敲低所致的生长抑制效应。此外，GGCT敲低在体内抑制了GSC的致瘤潜能。这些结果表明：由c-Jun促进表达的GGCT在GSC增殖和致瘤能力中起重要作用，且其敲低所致表型与Notch1减少相关。因此，GGCT可能成为靶向GSCs的新型治疗靶点。

原文链接：

γ-Glutamylcyclotransferase is transcriptionally regulated by c-Jun and controls proliferation of glioblastoma stem cells through Notch1 levels