2. Academic Validation
  3. Transcription Factor YY2 Inhibits Tumor Cell Glutamine Catabolism by Regulating GLS1 RNA Splicing Isoform GAC

Transcription Factor YY2 Inhibits Tumor Cell Glutamine Catabolism by Regulating GLS1 RNA Splicing Isoform GAC

  • Am J Pathol. 2025 Jul;195(7):1340-1357. doi: 10.1016/j.ajpath.2025.04.003.
Jingyi Liu 1,  Juan Li 1,  Yanjun Li 2,  Mankun Wei 1,  Debing Xiang 3,  Hezhao Zhao 4,  Makoto Miyagishi 5,  Vivi Kasim 6,  Shourong Wu 7
Affiliations

Affiliations

  • 1 Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
  • 2 College of Pharmacy and Biological Engineering, Chongqing University of Technology, Chongqing, China.
  • 3 Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing University, Chongqing, China.
  • 4 Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing University, Chongqing, China.
  • 5 Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan.
  • 6 Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. Electronic address: vivikasim@cqu.edu.cn.
  • 7 Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. Electronic address: shourongwu@cqu.edu.cn.
PMID: 40311755 DOI: 10.1016/j.ajpath.2025.04.003
Abstract

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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12683
    98.75%, Glutaminase Inhibitor