Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development of p53-deficient osteosarcoma

IF 4.5 2区医学 Q1 ONCOLOGY

Cancer Science Pub Date : 2024-06-26 DOI:10.1111/cas.16255

Tomoya Ueno, Shohei Otani, Yuki Date, Yu Katsuma, Yuma Nagayoshi, Tomoko Ito, Hiromi Ii, Susumu Kageyama, Susumu Nakata, Kosei Ito

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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.

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Myc上调Ggct、γ-谷氨酰环基转移酶，促进p53缺陷骨肉瘤的发展。

人类骨肉瘤（OS）的特点是 TP53 基因发生改变。在小鼠中，p53 基因缺失会诱发骨肉瘤，而 c-Myc（Myc）的致癌作用是不可或缺的。然而，人们对哪些基因是Myc促进肿瘤发生的靶基因知之甚少。在这里，我们研究了γ-谷氨酰环基转移酶（Ggct）在人类和小鼠OS发生过程中的作用，Ggct是谷胱甘肽平衡所必需的γ-谷氨酰循环的组成酶。我们发现，GGCT是人类OS的一个不良预后因素，而且删除Ggct可抑制小鼠p53缺陷性骨肉瘤的发生。Myc通过与Ggct启动子结合直接上调Ggct，通过基因组编辑删除其中的Myc结合位点可减轻p53缺陷型OS细胞的致瘤潜力。综上所述，这些结果表明了GGCT在癌细胞中广泛上调的合理性，并巩固了其作为抗癌药物靶点的适宜性。

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来源期刊

Cancer Science 医学-肿瘤学

自引率

3.50%

发文量

406

审稿时长

2 months

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.