{"title":"γ-谷氨酰环基转移酶受c-Jun转录调控,并通过Notch1水平控制胶质母细胞瘤干细胞的增殖。","authors":"Kozue Nose, Keiko Taniguchi, Mitsugu Fujita, Chiami Moyama, Masaya Mori, Mizuki Ishita, Tatsushi Yoshida, Hiromi Ii, Toshiyuki Sakai, Susumu Nakata","doi":"10.1038/s41417-024-00835-y","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 12","pages":"1-9"},"PeriodicalIF":4.8000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00835-y.pdf","citationCount":"0","resultStr":"{\"title\":\"γ-Glutamylcyclotransferase is transcriptionally regulated by c-Jun and controls proliferation of glioblastoma stem cells through Notch1 levels\",\"authors\":\"Kozue Nose, Keiko Taniguchi, Mitsugu Fujita, Chiami Moyama, Masaya Mori, Mizuki Ishita, Tatsushi Yoshida, Hiromi Ii, Toshiyuki Sakai, Susumu Nakata\",\"doi\":\"10.1038/s41417-024-00835-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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.\",\"PeriodicalId\":9577,\"journal\":{\"name\":\"Cancer gene therapy\",\"volume\":\"31 12\",\"pages\":\"1-9\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-10-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.nature.com/articles/s41417-024-00835-y.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer gene therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s41417-024-00835-y\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer gene therapy","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41417-024-00835-y","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
γ-Glutamylcyclotransferase is transcriptionally regulated by c-Jun and controls proliferation of glioblastoma stem cells through Notch1 levels
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.
期刊介绍:
Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair.
Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.