2. Academic Validation
  3. UMP functions as an endogenous regulator of NR4A1 to control gastric cancer progression

UMP functions as an endogenous regulator of NR4A1 to control gastric cancer progression

  • Mol Cell. 2025 Dec 4;85(23):4347-4364.e12. doi: 10.1016/j.molcel.2025.10.030.
Guodi Cai 1,  Zhenhua Zhang 1,  Lin Zhong 2,  Hong Wang 1,  Miaomiao Miao 1,  Jingtian Su 1,  Yana An 1,  Chenxi Zhang 1,  Xiaowei Luo 3,  Huai-Qiang Ju 4,  Jian Zhang 5,  Wanyi Huang 1,  Zhe Li 1,  Peiqing Liu 1,  Dinglan Wu 6,  Franky Leung Chan 7,  Huihao Zhou 1,  Fanghai Han 8,  Hong-Wu Chen 9,  Tao Su 10,  Junjian Wang 11
Affiliations

Affiliations

  • 1 National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 2 Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
  • 3 Institute of Marine Drugs, Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China.
  • 4 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou 510060, China.
  • 5 Thoracic Surgery Department, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 6 Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
  • 7 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 8 Department of Gastrointestinal Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China.
  • 9 Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, CA, USA. Electronic address: hwzchen@ucdavis.edu.
  • 10 Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: sutao@gzucm.edu.cn.
  • 11 National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: wangjj87@mail.sysu.edu.cn.
PMID: 41270758 DOI: 10.1016/j.molcel.2025.10.030
Abstract

Nucleotide metabolism reprogramming drives tumor progression, yet how tumor cells sense nucleotide levels remains unclear. Here, we identified UMP as an endogenous regulator of the Orphan Nuclear Receptor NR4A1 in gastric Cancer (GCa). Under UMP sufficiency, UMP directly binds to NR4A1, inhibiting its tumor-suppressive function and promoting GCa progression. Conversely, UMP deficiency resulting from disrupted pyrimidine biosynthesis derepresses NR4A1, which suppresses GCa cell survival and progression by both increasing NR4A1 occupancy at super-enhancers to reprogram survival-gene expression and enhancing NR4A1's pro-apoptotic activity at the mitochondria. NR4A1 loss was sufficient to rescue the effects of pyrimidine nucleotide stress on GCa cells in vitro and in vivo. NR4A1 agonists suppressed the pyrimidine salvage pathway triggered by de novo pyrimidine biosynthesis (DNPB) inhibition. Co-targeting DNPB and NR4A1 induced synergistic tumor lethality in GCa xenograft models. Together, our results establish UMP as an endogenous regulator of NR4A1 and provide an effective therapeutic strategy for GCa.

Keywords

DHODH; NR4A1; UMP; de novo pyrimidine biosynthesis pathway; gastric cancer.

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