ObjectiveThis study aims to study the effect of the enhancer of zeste homolog 2 (EZH2) inhibitor GSK126 on the proliferation and apoptosis of human tongue squamous cell carcinoma cellsin vitroand explore its related mechanisms in order to obtain insights into the clinical treatment of tongue squamous cell carcinoma.MethodsDifferent concentrations of GSK126 were applied to CAL-27 cells of tongue squamous cell carcinoma, and the effects of drugs on cell proliferation were detected through methyl thiazolyl tetrazolium (MTT) assay, colony formation assay, and 5-ethynyl-2’-deoxyuridine (EdU) fluorescence staining. Hoechst33342 fluorescence staining and the JC-1 method were used in observing apoptosis. The expression levels of extracellular regulated protein kinases (ERK), phospho-extracellular regulated protein kinases (p-ERK), Bax, Bcl-2, and Cleaved caspase-9 in Cal-27 cells were detected through Western blot.ResultsGSK126 inhibited CAL-27 cell proliferation and promoted apoptosis. GSK126 down-regulated the expression of p-ERK and Bcl-2 and increased the expression of Bax and Cleaved caspase-9 (P<0 .05).ConclusionGSK126 can inhibit the proliferation of CAL-27 cells in tongue squamous cell carcinoma and promote its apoptosis, and the related mechanism may be associated with the inhibition of the MEK/ERK signaling pathway and activation of the Bax/Bcl-2 pathway.