Epigenetic dysregulation, such as aberrant DNA methylation, is one of the hallmarks of cancer cells, however the mechanisms by which these dysregulations occur remain unclear. Previously, we found that DNA methyltransferase 3B (DNMT3B), which catalyzes cytosine methylation, is selectively oxidized by several stresses. A cysteine residue is the modification site on DNMT3B. As oxidation of DNMT3B attenuates its enzymatic activity, this reaction may be related to the epigenetic regulation. In this study, we focused on the cell cycle regulator CCND2 and examined whether its expression is regulated by oxidative stress and enzymatic activity of DNMT3B. Indeed, exposure to the stress and the universal DNMT inhibitor 5-aza-2'-deoxycytidine induced CCND2 expression. When DNMT1, DNMT3A, and DNMT3B were overexpressed, only DNMT3B significantly reduced CCND2 mRNA levels. CS mutant, which lost enzymatic activity, had no effect on CCND2 mRNA levels compared with the wild type. The siRNA knockdown of DNMT3B markedly enhanced CCND2 mRNA levels. Our data strongly suggest DNMT3B-specific regulation of CCND2 expression. Finally, bisulfite sequencing analysis revealed that oxidative stress significantly decreased DNA methylation levels in the CCND2 promoter region. These results indicate that oxidation of DNMT3B plays an important role in epigenetic regulation and may lead us to know the mechanism of epigenetic dysregulation in cancer cells.