2. Academic Validation
  3. STIP1 drives Metabolic Reprogramming in Esophageal Squamous Cell Carcinoma via AHCY-LDHA Axis

STIP1 drives Metabolic Reprogramming in Esophageal Squamous Cell Carcinoma via AHCY-LDHA Axis

  • Exploration (Beijing). 2025 May 25;5(5):20240198. doi: 10.1002/EXP.20240198.
Guoguo Jin 1 2 3 4,  Yanming Song 2,  Mingyang Yan 5 2,  Shaobo Fang 2 6,  Yang Shao 5 2,  Kexin Zhao 5 2,  Meng Liu 5 2,  Qinxin Guo 5 2,  Xinyang Jia 5 2,  Chengjuan Zhang 7,  Zhenwei Wang 5 2,  Kangdong Liu 5 2 4,  Xiang Li 5 2 4,  Simin Zhao 2 8 4,  Mee-Hyun Lee 2 9,  Zhiping Guo 1 3,  Zigang Dong 5 2 4
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Chronic Disease Management Fuwai Central China Cardiovascular Hospital Zhengzhou China.
  • 2 China-US (Henan) Hormel Cancer Institute Zhengzhou Henan China.
  • 3 Central China Subcenter of National Center for Cardiovascular Diseases Henan Cardiovascular Disease Center Fuwai Central-China Cardiovascular Hospital Central China Fuwai Hospital of Zhengzhou University Zhengzhou China.
  • 4 Tianjian Laboratory of Advanced Biomedical Sciences Institute of Advanced Biomedical Sciences Zhengzhou University Zhengzhou Henan China.
  • 5 Department of Pathophysiology School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan China.
  • 6 Department of Medical Imaging Zhengzhou University People's Hospital& Henan Provincial People's Hospital Zhengzhou China.
  • 7 Center of Bio Repository The Affiliated Cancer Hospital of Zhengzhou University Zhengzhou China.
  • 8 Affiliated Cancer Hospital of Zhengzhou University Zhengzhou Henan P.R. China.
  • 9 College of Korean Medicine Dongshin University Naju Republic of Korea.
PMID: 41163796 DOI: 10.1002/EXP.20240198
Abstract

Glucose metabolism reprogramming has emerged as a hallmark of Cancer. We have reported that high temperature food or drink (>65°C) is the key etiological factors contributing to esophageal squamous cell carcinoma (ESCC) progression. Intriguingly, we observed that heat stimulation (42°C) alters glycolytic pathways in esophagus cells, but the underlying mechanisms remain poorly understood. Our findings revealed that stress-induced phosphoprotein 1 (STIP1) exhibits elevated expression in esophageal tissues exposed to heat stimulation (>65°C) compared to unexposed tissues, and its overexpression correlated with clinical grade and predict poor prognosis in ESCC patients. Mechanistically, STIP1 interacts with and activates adenosylhomocysteinase (AHCY; also termed SAHH) and change the conformation of AHCY. STIP1 also facilitates AHCY binding to Lactate Dehydrogenase A (LDHA), stimulating glycolysis. Notably, AHCY recruits protein arginine methyltransferase 3 (PRMT3) to methylate LDHA at R106, inhibiting ubiquitination-mediated AHCY degradation. In vivo, STIP1 knockout in mice dramatically inhibits 4-nitrochinoline-oxide (4NQO) induced esophageal tumorigenesis. Through virtual screening and functional validation, we identified licochalcone A (LCA) as a potent inhibitor of STIP1-driven ESCC proliferation in vitro and in vivo. In summary, these findings delineate a pro-tumorigenic signaling pathway whereby heat-induced STIP1 upregulation promotes ESCC glycolysis and growth via moonlighting functions that coordinate AHCY activity and LDHA methylation.

Keywords

AHCY; ESCC; STIP1; glycolysis; heat stimulation.

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