Abstract: 【Abstract】 Objective To investigate the suppressive effect of histone deacetylase and DNA methyltransferase inhibitors on the malignant phenotype of human glioma cells by impacting on the epigenetic mechanism.Methods VPA (Valproic acid) was used as histone deacetylase inhibitor and Aza (5-aza-deoxycytidine) as DNA methyltransferase inhibitor. For in vitro study, U251 glioma cells were divided into four groups: the control group, VPA treatment group, Aza treatment group and the VPA+Aza combined treatment group. The proliferation activity of tumor cells was detected by MTT assay, cell cycle analysis by flow cytometry, apoptosis rate by Annexin V-FITC assay and the invasion ability of glioma cells by 2D Matrigel, 3D Matrigel, and transwell assay. The subcutaneous U251 tumor model was established in nude mice for in vivo study, xenografts were treated with VPA, Aza and VPA+Aza by multi-point local injection into tumor bed every 4 days within the observation period for 28 days and the gross tumor volume was measured. Results Compared with the control group, the tumor cell proliferation activity in VPA , Aza and VPA + Aza combined treatment group, was significantly lowered(P <0.05 for each group), the cells were arrested in G0/G1 phase, apoptotic cell rate was increased and cell invasion ability decreased significantly (P <0.05). The tumor volume in all treatment groups was much smaller than that in control group. The most significant effect on inhibition of malignant biological behaviour of glioma cells was observed in VPA + Aza combined treatment group. Conclusion To treat glioma cells with DNA methyltransferase and histone deacetylase inhibitors can reverse the malignant phenotype by inhibition of their epigenetic alterations, So this study provides the evidence that both of them can be developed as candidates for glioma treatment.

Key words: Glioma, histone deacetylase inhibitor, DNA methyltransferase inhibitor, Proliferation, Invasion, Apoptosis