Genistein (4', 5, 7-trihydroxyisoflavone) is an isoflavone compound obtained from plants that has potential applications in cancer therapy. However, the molecular mechanism of the action of genistein on cancer cell apoptosis is not well known. In this study, we investigated the effect of genistein on topoisomerase II-alpha (Topo II alpha), an important protein involved in the processes of DNA replication and cell proliferation. The results revealed that inhibition of Topo IIa expression through the regulation of Specificity protein 1 and Specificity protein 3 may be one of the reasons for genistein's induction of HeLa cell apoptosis.