The current study aimed to investigate the effect of valproic acid (VPA) on SOCS-1, SOCS-2, SOCS-3, SOCS-5, SOCS6, and SOCS-7 gene expression and cell growth inhibition in colon carcinoma IS1, IS2, and IS3 cell lines.Cancer is a process induced by the accumulation of epigenetic alterations such as DNA methylation and histone deacetylation. The DNA methylation and histone deacetylation of tumor suppressor genes (TSGs) have been shown in various cancers. The methylation and deacetylation of suppressors of the cytokine signaling (SOCS) family, as TSGs, have been demonstrated in numerous cancers. Histone deacetylase inhibitors (HDACIs) have emerged as accessory therapeutic agents for human cancers.IS1, IS2, and IS3 cells were cultured and treated with VPA. To determine cell viability, cell apoptosis, and the relative gene expression level, MTT assay, flow cytometry assay, and qRT-PCR, respectively, were performed. A database was established with the SPSS 16.0 software package (SPSS Inc., Chicago, Illinois, USA) for analysis. Data was acquired from three tests and is shown as means ± standard deviations. A significant difference was considered as p < 0.05.VPA changed the expression levels of the SOCS-1, SOCS-2, SOCS-3, SOCS-5, SOCS6, and SOCS-7 genes, by which cell apoptosis was induced and cell growth inhibited in all three cell lines (p < 0.0001).VPA can induce apoptosis through reactivation of SOCS-1, SOCS-2, SOCS-3, SOCS-5, SOCS6, and SOCS-7 gene expression.