Background: Enhancer of zeste homolog 2 (EZH2) has been shown to contribute to tumour development and/or progression. However, the signalling pathway underlying the regulation of EZH2 in nasopharyngeal carcinoma (NPC) remains unclear. Since EZH2 contains the putative Glycogen synthase kinase 3 beta (GSK3 beta) phosphorylation motif ADHWDSKNVSCKNC (591) and may act as a possible substrate of GSK-3 beta, it is possible that inactivation of GSK3 beta may lead to excessive EZH2 expression in NPC. Method: We first examined the expression of EZH2 and phosphorylated GSK3 beta (p-GSK3 beta) by immunohistochemical staining in NPC samples. Then, we evaluated the interaction of GSK3 beta and EZH2 using immunoprecipitation and immune blot. Moreover, we determined the effect of inhibition of GSK3 beta activity on EZH2 expression and tumor invasiveness in NPC cell lines in vitro. Finally, we evaluated the invasive properties of NPC cells after knocking down EZH2 expression with EZH2 siRNA. Results: We found that expression of EZH2 correlated with phosphorylated GSK3 beta (p-GSK3 beta) at Ser 9 (an inactivated form of GSK3 beta) in human nasopharyngeal carcinoma (NPC) samples. We also provided evidence that GSK3 beta is able to interact with EZH2 using immunoprecipitation and immune blot. Furthermore, we found that inhibition of GSK3 beta activity can lead to upregulation of EZH2 in NPC cell lines in vitro, with enhanced local invasiveness. By knocking down EZH2 expression with EZH2 siRNA, we found that these invasive properties were EZH2 dependent. Conclusion: Our findings indicate that GSK3 beta inactivation may account for EZH2 overexpression and subsequent tumour progression, and this mechanism might be a potential target for NPC therapy.