Interaction of PHGDH with IGF2BP1 facilitates m6A-dependent stabilization of TCF7L2 mRNA to confer multidrug resistance in gastric cancer.

Multidrug resistance (MDR) remains a significant barrier to effective chemotherapy and results in a poor prognosis for gastric cancer (GC). Exploring the mechanism of MDR is highly important for identifying biomarkers for MDR and developing new treatment strategies. In this study, integrative analyses of multiomics and bioinformatics data were combined with experimental validation to explore the mechanism of MDR in GC. We found that phosphoglycerate dehydrogenase (PHGDH), the key rate-limiting enzyme in the serine synthesis pathway, was significantly upregulated in MDR GC cells. PHGDH was found to perform a noncanonical function to promote MDR by activating the Wnt/β-catenin signaling pathway, and this effect is mediated by transcription factor 7-like 2 (TCF7L2), a pivotal co-activator of β-catenin in the Wnt pathway. Specifically, PHGDH stabilizes TCF7L2 mRNA by interacting with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), a key m6A reader, in an m6A-dependent manner, thereby increasing the expression of TCF7L2. Moreover, TCF7L2 binds to the promoter of PHGDH and regulates its expression, which forms a positive feedback loop. This PHGDH/IGF2BP1-TCF7L2 loop contributes to GC MDR and is correlated with a poor prognosis of GC patients.