TRIM8-dependent K63-ubiquitinated PGK1 promotes glycolysis and angiogenesis in gastric cancer via interaction with ACAT1

作者：Anqi Feng, Jianbin Zhang, Zeyu Wang, Zhukai Chen, Kang Fang, Zhaoxing Li, Hanyu Jiang, Zhuyun Leng, Shihan Zhang, Yuan Chu, Jingjing Lian, Tao Chen, Lechi Ye, Mei‐Dong Xu, Lingnan He · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08015-y · 被引用次数：4 · 研究领域：interferon and immune responses、Ubiquitin and proteasome pathways、Cancer, Hypoxia, and Metabolism

Glycolysis is crucial for promoting cancer progression. However, the precise mechanism underlying glycolysis regulating the angiogenic process remains to be defined. Here, we demonstrate that in human gastric cancer cells, the E3 ligase TRIM8 promotes the K63-linked ubiquitination of the glycolytic enzyme PGK1 and improves its stability, which leads to acetyltransferase ACAT1 recruitment, increased interaction of PGK1 with ACAT1, and subsequent PGK1 acetylation-dependent glycolytic activity. This activity facilitates PGK1-mediated glycolysis, lactate accumulation and triggers a significant increase in endothelial cell migration and tube formation, which ultimately accelerates tumor angiogenesis in gastric cancer. TRIM8 levels are positively correlated with tumor angiogenesis and poor prognosis in gastric cancer patients. These findings elucidate a novel mechanism underlying the upregulation of angiogenesis mediated by K63 ubiquitination-regulated glycolysis in tumor cells and provide a molecular basis for eliminating gastric cancer angiogenesis by targeting TRIM8-dependent PGK1 K63 ubiquitination.