Jingyi Liu , Juan Li , Yanjun Li , Mankun Wei , Debing Xiang , Hezhao Zhao , Makoto Miyagishi , Vivi Kasim , Shourong Wu
{"title":"转录因子YY2通过调节GLS1 RNA剪接异构体GAC抑制肿瘤细胞谷氨酰胺分解代谢。","authors":"Jingyi Liu , Juan Li , Yanjun Li , Mankun Wei , Debing Xiang , Hezhao Zhao , Makoto Miyagishi , Vivi Kasim , Shourong Wu","doi":"10.1016/j.ajpath.2025.04.003","DOIUrl":null,"url":null,"abstract":"<div><div>The metabolic reprogramming of amino acids is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, colorectal cancer and hepatocarcinoma cells were used to show that Yin yang 2 (YY2) significantly reduced the transcriptional activity of glutaminase 1 (<em>GLS1</em>), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C, a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and <em>de novo</em> glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, YY2/GLS1–mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential <em>in vivo</em>. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identified YY2/glutaminase C as a negative regulator of glutamine catabolism in tumor cells and revealed a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1340-1357"},"PeriodicalIF":3.6000,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transcription Factor YY2 Inhibits Tumor Cell Glutamine Catabolism by Regulating GLS1 RNA Splicing Isoform GAC\",\"authors\":\"Jingyi Liu , Juan Li , Yanjun Li , Mankun Wei , Debing Xiang , Hezhao Zhao , Makoto Miyagishi , Vivi Kasim , Shourong Wu\",\"doi\":\"10.1016/j.ajpath.2025.04.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The metabolic reprogramming of amino acids is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, colorectal cancer and hepatocarcinoma cells were used to show that Yin yang 2 (YY2) significantly reduced the transcriptional activity of glutaminase 1 (<em>GLS1</em>), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C, a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and <em>de novo</em> glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, YY2/GLS1–mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential <em>in vivo</em>. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identified YY2/glutaminase C as a negative regulator of glutamine catabolism in tumor cells and revealed a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.</div></div>\",\"PeriodicalId\":7623,\"journal\":{\"name\":\"American Journal of Pathology\",\"volume\":\"195 7\",\"pages\":\"Pages 1340-1357\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-04-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0002944025001427\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0002944025001427","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
The metabolic reprogramming of amino acids is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, colorectal cancer and hepatocarcinoma cells were used to show that Yin yang 2 (YY2) significantly reduced the transcriptional activity of glutaminase 1 (GLS1), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C, a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and de novo glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, YY2/GLS1–mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential in vivo. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identified YY2/glutaminase C as a negative regulator of glutamine catabolism in tumor cells and revealed a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.