Histone post-translational modifications (HPTMs) play a major role in control of gene transcription. Among them, histone acetylation and methylation have been extensively investigated. Histone acetylation at different residues is generally associated to active gene transcription. In contrast, histone methylation can be associated either to transcriptional activation or repression, depending primarily on the histone residue that is subjected to the modification. Herein, effects of the histone deacetylase inhibitor SAHA on the sodium-iodide symporter (NIS) gene expression were investigated in breast cancer cells (MDA157 and MDA468). SAHA treatment induces high increase of NIS mRNA levels in MDA468 cells (300-fold), but moderate increase in MDA157 cells (fivefold). Histone H3 HPTMs (acetylation and methylations) on transcriptional units of NIS gene were investigated in these cell lines upon SAHA treatment. Our data indicate that HPTMs, particularly the H3 lysine 27 trimethylation, may operate in contrast to current models that relate epigenetic modifications with transcriptional activity.