TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1
Chao Gu, Yiwen Xia, Chen Lu, Shengkui Qiu, Jihuan Wang, Lu Zhang, Jialun Lv, Tianlu Jiang, Lang Fang, Penghui Xu, Zetian Chen, Y. Li, Li Xie, Zekuan Xu, Bowen Li
Abstract
. Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC.