Glutamic-pyruvic transaminase 1 deficiency-mediated metabolic reprogramming facilitates colorectal adenoma-carcinoma progression

  • Sci Transl Med. 2025 Jan;17(779):eadp9805. doi: 10.1126/scitranslmed.adp9805.
Li Xiong  1  2  3 ,  Xin Yang  1  2  3 ,  Huashan Liu  1  2  3 ,  Xianrui Wu  4 ,  Tanxing Cai  1  2  3 ,  Ming Yuan  1  2  3 ,  Liang Huang  1  2  3 ,  Chi Zhou  5 ,  Xiaobin Zheng  1  2  3 ,  Wenxin Li  1  2  3 ,  Ziwei Zeng  1  2  3 ,  Shujuan Li  6 ,  Ping Lan  1  2  3 ,  Liang Kang  1  2  3 ,  Zhenxing Liang  1  2  3
Affiliations
  • 1. Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
  • 2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
  • 3. Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
  • 4. Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.
  • 5. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510050, China.
  • 6. Department of Pharmacy, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
PMID: 39742507 DOI: 10.1126/scitranslmed.adp9805
Abstract

The tumorigenesis of colorectal Cancer (CRC) often follows the normal-adenoma-carcinoma (N-A-C) sequence. However, the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown. Here, we analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC, revealing that glutamic-pyruvic transaminase 1 (GPT1) in colorectal tissues was down-regulated during the N-A-C process and correlated with poor CRC prognosis. Mechanistically, GPT1 was transcriptionally activated by Krüppel-like factor 4 (KLF4). GPT1 reprogrammed metabolism and suppressed CRC tumorigenesis in cells and mouse models not only through enzyme-dependent α-ketoglutarate (α-KG) production and Wnt signaling inhibition but also through enzyme-independent disruption of the folate cycle through binding with methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L). Furthermore, we identified poliumoside as a GPT1 activator that restrained CRC progression in cells, patient-derived CRC organoids, and patient-derived xenograft (PDX) models of CRC. Our study uncovers a role for GPT1 in CRC tumorigenesis and shows that poliumoside is a potential drug for the prevention and treatment of CRC.

Products