RRC ID 82775
Author Ueno T, Otani S, Date Y, Katsuma Y, Nagayoshi Y, Ito T, Ii H, Kageyama S, Nakata S, Ito K.
Title Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development of p53-deficient osteosarcoma.
Journal Cancer Sci
Abstract Osteosarcoma (OS) in humans is characterized by alterations in the TP53 gene. In mice, loss of p53 triggers OS development, for which c-Myc (Myc) oncogenicity is indispensable. However, little is known about which genes are targeted by Myc to promote tumorigenesis. Here, we examined the role of γ-glutamylcyclotransferase (Ggct) which is a component enzyme of the γ-glutamyl cycle essential for glutathione homeostasis, in human and mouse OS development. We found that GGCT is a poor prognostic factor for human OS, and that deletion of Ggct suppresses p53-deficient osteosarcomagenesis in mice. Myc upregulates Ggct directly by binding to the Ggct promoter, and deletion of a Myc binding site therein by genome editing attenuated the tumorigenic potential of p53-deficient OS cells. Taken together, these results show a rationale that GGCT is widely upregulated in cancer cells and solidify its suitability as a target for anticancer drugs.
Volume 115(9)
Pages 2961-2971
Published 2024-9-1
DOI 10.1111/cas.16255
PMID 38924236
PMC PMC11462974
MeSH Animals Bone Neoplasms* / genetics Bone Neoplasms* / metabolism Bone Neoplasms* / pathology Carcinogenesis / genetics Cell Line, Tumor Female Gene Expression Regulation, Neoplastic Humans Male Mice Osteosarcoma* / genetics Osteosarcoma* / metabolism Osteosarcoma* / pathology Prognosis Promoter Regions, Genetic / genetics Proto-Oncogene Proteins c-myc* / genetics Proto-Oncogene Proteins c-myc* / metabolism Tumor Suppressor Protein p53* / genetics Tumor Suppressor Protein p53* / metabolism Up-Regulation* gamma-Glutamylcyclotransferase* / genetics gamma-Glutamylcyclotransferase* / metabolism
Resource
Human and Animal Cells NOS-1(RCB1032)