Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development ofp53-deficient osteosarcoma

Abstract

SUMMARYOsteosarcoma (OS) in humans is characterized by alterations in theTP53gene. 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 Ggct, γ-glutamylcyclotransferase which is a component enzyme of γ-glutamyl cycle essential for glutathione homeostasis, in human and mouse OS development. We found thatGGCTis a poor prognostic factor for human OS, and that deletion ofGgctsuppressesp53-deficient osteosarcomagenesis in mice. Myc upregulates Ggct directly by binding to theGgctpromoter, and deletion of a Myc binding site therein by genome editing attenuated the tumorigenic potential ofp53- 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.