A schematic model illustrating that LCA can inhibit ESCC growth by inhibiting the STIP1/AHCY/LDHA axis. In brief. Jin et al. demonstrated that targeting STIP1 can significantly inhibit the progression of esophageal squamous cell carcinoma. The high expression of STIP1 increased the interaction between AHCY and LDHA and then AHCY recruits PRMT3 to methylate LDHA at R106 to promote the proliferation of cancer cells. LCA can inhibit the STIP1/AHCY/LDHA axis and inhibit tumor development mediated by the gly.
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.
Author list:
Guoguo Jin*†, Yanming Song†, Mingyang Yan†, Shaobo Fang, Yang Shao, Kexin Zhao, Meng Liu, Qinxin Guo, Xinyang Jia, Chengjuan Zhang, Zhenwei Wang, Kangdong Liu, Xiang Li, Simin Zhao, Mee-Hyun Lee, Zhiping Guo*, Zigang Dong*
How to cite:
G. Jin, Y. Song, M. Yan, S. Fang, Y. Shao, K. Zhao, M. Liu, Q. Guo, X. Jia, C. Zhang, Z. Wang, K. Liu, X. Li, S. Zhao, M.-H. Lee, Z. Guo, Z. Dong, Exploration 2025, 20240198.
https://doi.org/10.1002/EXP.20240198