Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development of p53-deficient osteosarcoma.
Tomoya UenoShohei OtaniYuki DateYu KatsumaYuma NagayoshiTomoko ItoHiromi IiSusumu KageyamaSusumu NakataKosei ItoPublished in: Cancer science (2024)
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.
Keyphrases
- transcription factor
- genome editing
- endothelial cells
- crispr cas
- prognostic factors
- wild type
- induced apoptosis
- genome wide identification
- dna methylation
- induced pluripotent stem cells
- gene expression
- signaling pathway
- high fat diet induced
- pluripotent stem cells
- clinical trial
- type diabetes
- oxidative stress
- cell cycle arrest
- climate change
- adipose tissue
- endoplasmic reticulum stress