TFAP4 Promotes Glycolysis and Chemoresistance via Transcriptional Activation of PSAT1 in Colon Cancer

Colon cancer (CC) is a worldwide prevalent malignant tumor whose progression is critically driven by chemoresistance and metabolic dysregulation. While phosphoserine aminotransferase 1 (PSAT1) shows upregulated expression in CC tissues, its potential role in metabolic reprogramming and chemotherapy resistance requires further investigation.We evaluated PSAT1 expression through integrated bioinformatics analysis and clinical tissue validation. Mechanistic studies involved GSEA on PSAT1, transcription factor screening via ChIPBase3 and JASPAR databases, and experimental validation via ChIP and dual-luciferase reporter assays. Functional assessments included glycolytic parameter measurement using Seahorse XFe96 system and assay kits, malignant phenotype evaluation through colony formation and Transwell assays, cisplatin sensitivity testing through CCK8 assays, analysis of cell proliferation upon cisplatin treatment through colony formation and flow cytometry, and examination of glycolytic enzymes and drug resistance-related pathways by Western blot. The roles of PSAT1 in glycolysis, chemoresistance, and tumor progression were validated in xenograft mouse models. PSAT1 was significantly overexpressed in CC and correlated positively with glycolytic activity. In vitro , PSAT1 knockdown suppressed glycolysis in HT-29 cells, impaired malignant phenotypes, and enhanced their chemosensitivity. TFAP4 was found to activate glycolysis and trigger chemoresistance by transcriptionally regulating PSAT1. In vivo , PSAT1 knockdown inhibited tumor growth, glycolytic protein expression, and the activation of chemoresistance pathways.TFAP4 promotes glycolysis and induces chemoresistance in CC by transcriptionally activating PSAT1, accelerating malignant tumor progression. The findings offer new biomarkers for CC therapies.