Background <p>The study aimed to investigate polycomb group factor 1 (PCGF1) expression in colon cancer and its mechanism of action in the proliferation and migration of colon cancer cells.</p> Method <p>In this study, PCGF1 expression in colon cancer and the association between PCGF1 expression and the survival prognosis of patients with colon cancer were analyzed using the cancer genome atlas (TCGA) database. Furthermore, PCGF1 expression in normal colon epithelial cells and colon cancer cells was examined. A PCGF1 knockdown cell model was developed using HCT116 and HT29 cell lines. The effect of PCGF1 on cell proliferation was evaluated via CCK-8 and clone formation assays. In addition, the effect of PCGF1 on cell invasive and migratory abilities was explored via scratch and Transwell experiments, and the expression levels of EMT-related proteins was analyzed via immunoblotting assay.</p> Results <p>PCGF1 expression significantly increased in colon cancer tissues. This expression was also found to be closely associated with tumor staging of patients with colon cancer. High PCGF1 expression showed negative correlation with overall survival rate in these patients. The proliferative ability of HCT116 and HT29 cells knocked down by PCGF1 weakened, colony formation was reduced, and cell invasive and migratory capabilities diminished. Meanwhile, the expressions of EMT-related proteins, such as N-cadherin and Snail1, were remarkably downregulated in PCGF1 knockdown cells, whereas that of E-cadherin was significantly upregulated. Moreover, PCGF1 knockdown led to a strongly decrease in the phosphorylation levels of PI3K, Akt and mTOR proteins and in the levels of β-catenin and c-Myc.</p> Conclusion <p>PCGF1 may promote the proliferation and EMT process in HCT116 and HT29 cells by activating the Wnt/β-catenin and PI3K/Akt/mTOR signaling pathway.</p>