Monoclonal antibodies (mAbs) are crucial in pharmaceutical biotechnology. Mammalian cell lines are the most preferred for their production. One of the significant challenging issues of mammalian expression systems is epigenetic gene silencing. Employing epigenetic gene regulation tools can increase the productivity of the mammalian cell lines. Sodium butyrate (NaBut) and valproic acid (VPA) regulate gene expression by inhibiting histone deacetylase. A ubiquitous chromatin-opening element (UCOE) can improve expression by reducing DNA methylation. Here, the separate and combined effects of NaBut and VPA histone deacetylase inhibitors (iHDACs) and UCOE on mAb synthesis were studied. Stable cell lines were generated by non-UCOE (CHO-HL) and UCOE-containing vectors (CHO-UHUL) and cultured in the presence and absence of NaBut or VPA. Expression analysis showed that CHO-UHUL gave a 4-fold greater yield than non-UCOE CHO-HL. Antibody production levels of the CHO-HL and CHO-UHUL cells increased 2-fold and 2.5-fold after NaBut and VPA treatment, respectively. These results indicate that UCOE has more impact on antibody expression than iHDACs. iHDAC treatment exhibited at least a 0.5-fold higher antibody yield in UCOE containing CHO-UHUL cells. Thus utilization of NaBut and VPA (iHDACs) and UCOE resulted in antibody expression improvement, and the combined use of them had a synergistic effect on antibody synthesis.