Hepatocarcinoma is the most common malignant tumor of the liver and the third leading cause of cancer related deaths worldwide. The incidence of hepatocarcinoma is characterized by concealment, cell heterogeneity and drug resistance, and the tumor is prone to invasion, metastasis and recurrence, which makes the clinical treatment effect of hepatocarcinoma poor. Transcription factor AP-2α plays an important role as a tumor suppressor in hepatocarcinoma, whose expression is positively correlated with the prognosis of hepatocarcinoma patients. SOX9 plays a major role in cell differentiation, sex determination and tumorigenesis. The abnormal increase of SOX9 was found in liver cancer, which promoted the growth of cancer cells. In our study, we used JASPAR software analysis to predict the potential binding sites of AP-2α in the promoter region of the SOX9 gene. The potential binding site of AP-2α was confirmed by luciferase assays and electrophoretic mobility shift assay(EMSA). AP-2α can directly bind to the promoter region of the SOX9 gene and inhibit its transcription activity. We found that AP-2α suppresses the expression of SOX9 at both mRNA and protein levels by real-time quantitative PCR and Western blots. These results revealed that AP-2α binds to the promoter region of the SOX9 gene, and negatively regulates the expression of oncogene SOX9 in hepatocarcinoma cells.